Nitroxide-mediated radical polymerization is a method of radical polymerization that makes use of an
nitroxide
Aminoxyl denotes a radical functional group with general structure R2N–O•. It is commonly known as a nitroxyl radical or a nitroxide, however IUPAC discourages the use of these terms, as they erroneously suggest the presence of a nitro group. ...
initiator to generate polymers with well controlled
stereochemistry
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereois ...
and a very low
dispersity
In chemistry, the dispersity is a measure of the heterogeneity of sizes of molecules or particles in a mixture. A collection of objects is called uniform if the objects have the same size, shape, or mass. A sample of objects that have an inconsi ...
. It is a type of
reversible-deactivation radical polymerization
Reversible deactivation radical polymerizations (RDRPs) are members of the class of reversible deactivation polymerizations which exhibit much of the character of living polymerizations, but cannot be categorized as such as they are not without cha ...
.
Alkoxyamine Initiators
The initiating materials for nitroxide-mediated
radical polymerization
In polymer chemistry, free-radical polymerization (FRP) is a method of polymerization by which a polymer forms by the successive addition of free-radical building blocks (repeat units). Free radicals can be formed by a number of different mechanis ...
(NMP) are a family of compounds referred to as alkoxyamines. An alkoxyamine can essentially be viewed as an
alcohol
Alcohol most commonly refers to:
* Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom
* Alcohol (drug), an intoxicant found in alcoholic drinks
Alcohol may also refer to:
Chemicals
* Ethanol, one of sev ...
bound to a secondary
amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...
by an N-O
single bond
In chemistry, a single bond is a chemical bond between two atoms involving two valence electrons. That is, the atoms share one pair of electrons where the bond forms. Therefore, a single bond is a type of covalent bond. When shared, each of th ...
. The utility of this
functional group
In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the rest ...
is that under certain conditions,
homolysis of the C-O bond can occur, yielding a stable radical in the form of a 2-center 3-electron N-O system and a carbon
radical
Radical may refer to:
Politics and ideology Politics
*Radical politics, the political intent of fundamental societal change
*Radicalism (historical), the Radical Movement that began in late 18th century Britain and spread to continental Europe and ...
which serves as an initiator for radical polymerization. For the purposes of NMP, the R groups attached to the
nitrogen
Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...
are always bulky,
sterically hindering groups and the R group in the O- position forms a stable radical, generally is
benzylic
In organic chemistry, benzyl is the substituent or molecular fragment possessing the structure . Benzyl features a benzene ring () attached to a methylene group () group.
Nomenclature
In IUPAC nomenclature, the prefix benzyl refers to a substi ...
for polymerization to occur successfully. NMP allows for excellent control of chain length and structure, as well as a relative lack of true termination that allows polymerization to continue as long as there is available
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 ...
. Because of this it is said to be “living".
Persistent radical effect
The living nature of NMP is due to the
persistent radical effect (PRE). The PRE is a phenomenon observable in some radical systems which leads to the highly favored formation of one product to the near exclusion of other radical couplings due to one of the radical species being particularly stable, existing in greater and greater concentrations as the reaction progresses while the other one is transient, reacting quickly with either itself in a termination step or with the persistent radical to form a desired product. As time goes on, a higher concentration of the persistent radical is present, which couples reversibly with itself, meaning that any of the transient radical still present tends to couple with the persistent radical rather than itself due to greater availability. This leads to a greater proportion of cross-coupling than self-coupling in radical species.
In the case of a nitroxide-mediated polymerization reaction, the persistent radical is the nitroxide species and the transient radical is always the carbon radical. This leads to repeated coupling of the nitroxide to the growing end of the polymer chain, which would ordinarily be considered a termination step, but is in this case reversible. Because of the high rate of coupling of the nitroxide to the growing chain end, there is little coupling of two active growing chains, which would be an irreversible terminating step limiting the chain length. The nitroxide binds and unbinds to the growing chain, protecting it from termination steps. This ensures that any available monomer can be easily scavenged by active chains. Because this polymerization process does not naturally self-terminate, this polymerization process is described as “living,” as the chains continue to grow under suitable reaction conditions whenever there is reactive monomer to “feed” them. Because of the PRE, it can be assumed that at any given time, almost all of the growing chains are “capped” by a mediating nitroxide, meaning that they dissociate and grow at very similar rates, creating a largely uniform chain length and structure.
Nitroxide stability
As stated above,
nitroxide
Aminoxyl denotes a radical functional group with general structure R2N–O•. It is commonly known as a nitroxyl radical or a nitroxide, however IUPAC discourages the use of these terms, as they erroneously suggest the presence of a nitro group. ...
radicals are effective mediators of well-controlled radical polymerization because they are quite stable, allowing them to act as persistent radicals in a reaction mixture. This
stability
Stability may refer to:
Mathematics
*Stability theory, the study of the stability of solutions to differential equations and dynamical systems
**Asymptotic stability
**Linear stability
**Lyapunov stability
**Orbital stability
**Structural stabilit ...
is a result of their unique structure. In most diagrams, the radical is depicted on the oxygen, but another resonance structure exists which is more helpful in explaining their stability in which the radical is on the nitrogen, which has a double bond to the oxygen. In addition to this
resonance
Resonance describes the phenomenon of increased amplitude that occurs when the frequency of an applied periodic force (or a Fourier component of it) is equal or close to a natural frequency of the system on which it acts. When an oscillatin ...
stability, nitroxides used in NMRP always contain bulky, sterically hindering groups in the R1 and R2 positions. The significant steric bulk of these substituents entirely prevents radical coupling in the N-centered resonance form while significantly reducing it in the O-centered form. These bulky groups contribute stability, but only if there is no resonance provided by allyl or aromatic groups α to the N. These result in decreased stability of the nitroxide, presumably because they offer less sterically hindered sites for radical coupling to take place. The resulting inactivity of the radical makes hemolytic cleavage of the alkoxyamine quite fast in more sterically hindered species.
Nitroxide choice
The choice of a specific nitroxide species to use has a large effect on the efficacy of an attempted polymerization. An effective polymerization (fast rate of chain growth, consistent chain length) results from a nitroxide with a fast C-O homolysis and relatively few side reactions. A more polar solvent lends itself better to C-O homolysis, so polar solvents which cannot bind to a labile nitroxide are the most effective for NMP. It is generally agreed that the structural factor that has the greatest effect on the ability of a nitroxide to mediate a radical polymerization is steric bulk. Generally speaking, greater steric bulk on the nitroxide leads to greater strain on the alkoxyamine, leading to the most easily broken bond, the C-O single bond, cleaving homolytically.
Ring size
In the case of cyclic nitroxides, five-membered ring systems have been shown to cleave more slowly than six-membered rings and acyclic nitroxides with t-butyl moieties as their R groups cleaved fastest of all. This difference in the rate of cleavage was determined to result not from a difference in C-O bond lengths, but in the difference of C-O-N bond angle in the alkoxyamine. The smaller the bond angle the greater the steric interaction between the nitroxide and the alkyl fragment and the more easily the initiator species broke apart.
Steric bulk
The efficiency of polymerization increases more and more with increased steric bulk of the nitroxide up to a point.
TEMPO
In musical terminology, tempo (Italian, 'time'; plural ''tempos'', or ''tempi'' from the Italian plural) is the speed or pace of a given piece. In classical music, tempo is typically indicated with an instruction at the start of a piece (often ...
((2,2,6,6-Tetramethylpiperidin-1-yl)oxyl) is capable of inducing the
polymerization of styrene and
styrene
Styrene () is an organic compound with the chemical formula C6H5CH=CH2. This derivative of benzene is a colorless oily liquid, although aged samples can appear yellowish. The compound evaporates easily and has a sweet smell, although high concen ...
derivatives fairly easily, but is not sufficiently labile to induce polymerization of
butyl acrylate
Butyl acrylate is an organic compound with the formula C4H9O2CCH=CH2. A colorless liquid, it is the butyl ester of acrylic acid. It is used commercially on a large scale as a precursor to polybutylacrylate, which is used in paints, sealants, coa ...
under most conditions. TEMPO derivatives with even bulkier groups at the positions α to N have a rate of homolysis great enough to induce NMP of butyl acrylate, and the bulkier the α groups, the faster polymerization occurs. This indicates that the steric bulk of the nitroxide fragment can be a good indicator of the strength of an alkoxyamine initiator, at least up to a point. The equilibrium of its homolysis and reformation favors the radical form to the extent that recombination to reform an alkoxyamine over the course of NMP occurs too slowly to maintain control of chain length.
Preparation methods
Because TEMPO, which is commercially available, is a sufficient nitroxide mediator for the synthesis of polystyrene derivatives, the preparation of alkoxyamine initiators for NMP of copolymers is in many cases a matter of attaching a nitroxide group (TEMPO) to a specifically synthesized alkyl fragment. Several methods have been reported to achieve this transformation.
Jacobsen's catalyst
Jacobsen's catalyst
Jacobsen's catalyst is the common name for N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(III) chloride, a coordination compound of manganese and a salen-type ligand. It is used as an asymmetric catalyst in the Jacobs ...
is a
manganese
Manganese is a chemical element with the symbol Mn and atomic number 25. It is a hard, brittle, silvery metal, often found in minerals in combination with iron. Manganese is a transition metal with a multifaceted array of industrial alloy use ...
-based
catalyst
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
commonly used for the
stereoselective
In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during a non-stereospecific creation of a new stereocenter or during a non-stereospecific transformation of ...
epoxidation of
alkenes
In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond.
Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...
. This
epoxidation
In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale for ...
proceeds by a radical addition mechanism, which can be taken advantage of by introducing the radical TEMPO group into the reaction mixture. After treatment with a mild
reducing agent
In chemistry, a reducing agent (also known as a reductant, reducer, or electron donor) is a chemical species that "donates" an electron to an (called the , , , or ).
Examples of substances that are commonly reducing agents include the Earth meta ...
such as
sodium borohydride
Sodium borohydride, also known as sodium tetrahydridoborate and sodium tetrahydroborate, is an inorganic compound with the formula Na BH4. This white solid, usually encountered as an aqueous basic solution, is a reducing agent that finds appli ...
, this yields the product of a
Markovnikov Markovnikov (russian: Марковников) is a Russian masculine surname, which originates from ''морковь'' (''carrot''); its feminine counterpart is Markovnikova. It may refer to
*Vladimir Markovnikov (1837–1904), Russian chemist
*Niko ...
addition of nitroxide to the alkene. Jacobsen’s catalyst is fairly mild, and a wide variety of functionalities on the alkene
substrate can be tolerated. Practical
yields are not necessarily as high as those reported by Dao et al., however.
Hydrazine
An alternative method is to react a substrate with a C-Br bond at the desired location of the nitroxide with
hydrazine
Hydrazine is an inorganic compound with the chemical formula . It is a simple pnictogen hydride, and is a colourless flammable liquid with an ammonia-like odour. Hydrazine is highly toxic unless handled in solution as, for example, hydrazine ...
, generating an alkyl substituted hydrazine which is then exposed to a nitroxide radical and a mild
oxidating agent such as
lead dioxide
Lead(IV) oxide is the inorganic compound with the formula PbO2. It is an oxide where lead is in an oxidation state of +4. It is a dark-brown solid which is insoluble in water. It exists in two crystalline forms. It has several important applicatio ...
. This generates a carbon-centered radical which couples with the nitroxide to generate the desired alkoxyamine. This method has the disadvantage of being relatively inefficient for some species, as well as the inherent danger of having to work with extremely toxic hydrazine and the inconvenience of having to run reactions in inert atmosphere.
Treatment of aldehydes with hydrogen peroxide
Yet another published alkoxyamine synthesis involves treatment of
aldehydes
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 group ...
with
hydrogen peroxide
Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3% ...
, which adds to the carbonyl group. The resulting species rearranges in situ in the presence of
CuCl forming formic acid and the desired alkyl radical, which couples with tempo to produce the target alkoxyamine. The reaction appears to give fairly good yields and tolerates a variety of
functional groups
In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the rest ...
in the alkyl chain.
Electrophilic bromination and nucleophilic attack
A synthesis has been described by Moon and Kang consisting of a
one-electron reduction
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
of a nitroxide radical in metallic
sodium
Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable iso ...
to yield a nucleophilic nitroxide. The nitroxide nucleophile is then added to an appropriate
alkyl bromide
Organobromine compounds, also called organobromides, are organic compounds that contain carbon Chemical bond, bonded to bromine. The most pervasive is the naturally produced bromomethane.
One prominent application of synthetic organobromine comp ...
, yielding the alkoxyamine by a simple
SN2 reaction
The SN2 reaction is a type of reaction mechanism that is common in organic chemistry. In this mechanism, one bond is broken and one bond is formed in a concerted way, i.e., in one step. The name SN2 refers to the Hughes-Ingold symbol of the m ...
. This technique has the advantage of requiring only the appropriate alkyl bromide to be synthesized without requiring inconvenient reaction conditions and extremely hazardous reagents like Braso et al.’s method.
[Moon, B., Minjyuk, K. Macromol. Res., 2005, 13(3), 229–235.]
References
Polymerization reactions