Nitroxide-mediated radical polymerization

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Nitroxide-mediated radical polymerization is a method of radical polymerization that makes use of an nitroxide initiator to generate polymers with well controlled stereochemistry and a very low dispersity. [1] It is a type of reversible-deactivation radical polymerization.

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A chain growth step in a nitroxide mediated polymerization process. Nitroxide reaction3.gif
A chain growth step in a nitroxide mediated polymerization process.

Alkoxyamine Initiators

The initiating materials for nitroxide-mediated radical polymerization (NMP) are a family of compounds referred to as alkoxyamines. An alkoxyamine can essentially be viewed as an alcohol bound to a secondary amine by an N-O single bond. The utility of this functional group 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 which serves as an initiator for radical polymerization. [2] For the purposes of NMP, the R groups attached to the nitrogen are always bulky, sterically hindering groups and the R group in the O- position forms a stable radical, generally is benzylic 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. 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). [3] 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. [4]

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. [5]

Nitroxide stability

As stated above, nitroxide 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 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 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. [6] The resulting inactivity of the radical makes hemolytic cleavage of the alkoxyamine quite fast in more sterically hindered species. [7]

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. [8]

Steric bulk

The efficiency of polymerization increases more and more with increased steric bulk of the nitroxide up to a point. TEMPO ((2,2,6,6-Tetramethylpiperidin-1-yl)oxyl) is capable of inducing the polymerization of styrene and styrene derivatives fairly easily, but is not sufficiently labile to induce polymerization of butyl acrylate 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. [9]

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 is a manganese-based catalyst commonly used for the stereoselective epoxidation of alkenes. This epoxidation 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 such as sodium borohydride, this yields the product of a Markovnikov 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. [10]

Hydrazine

An alternative method is to react a substrate with a C-Br bond at the desired location of the nitroxide with hydrazine, generating an alkyl substituted hydrazine which is then exposed to a nitroxide radical and a mild oxidating agent such as lead dioxide. 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. [11]

Treatment of aldehydes with hydrogen peroxide

Yet another published alkoxyamine synthesis involves treatment of aldehydes with hydrogen peroxide, 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 the alkyl chain. [12]

Electrophilic bromination and nucleophilic attack

A synthesis has been described by Moon and Kang consisting of a one-electron reduction of a nitroxide radical in metallic sodium to yield a nucleophilic nitroxide. The nitroxide nucleophile is then added to an appropriate alkyl bromide, yielding the alkoxyamine by a simple SN2 reaction. 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. [13]

Related Research Articles

In polymer chemistry, living polymerization is a form of chain growth polymerization where the ability of a growing polymer chain to terminate has been removed. This can be accomplished in a variety of ways. Chain termination and chain transfer reactions are absent and the rate of chain initiation is also much larger than the rate of chain propagation. The result is that the polymer chains grow at a more constant rate than seen in traditional chain polymerization and their lengths remain very similar. Living polymerization is a popular method for synthesizing block copolymers since the polymer can be synthesized in stages, each stage containing a different monomer. Additional advantages are predetermined molar mass and control over end-groups.

Organolithium reagent

Organolithium reagents are organometallic compounds that contain carbon – lithium 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.

In chemistry, homolysis or homolytic fission is chemical bond dissociation of a molecular bond by a process where each of the fragments retains one of the originally bonded electrons. During homolytic fission of a neutral molecule with an even number of electrons, two free radicals will be generated. That is, the two electrons involved in the original bond are distributed between the two fragment species. The energy involved in this process is called bond dissociation energy (BDE). Bond cleavage is also possible by a process called heterolysis.

Free-radical polymerization (FRP) is a method of polymerization, by which a polymer forms by the successive addition of free-radical building blocks. Free radicals can be formed by a number of different mechanisms, usually involving separate initiator molecules. Following its generation, the initiating free radical adds (nonradical) monomer units, thereby growing the polymer chain.

The Barton–McCombie deoxygenation is an organic reaction in which a hydroxy functional group in an organic compound is replaced by a hydrogen to give an alkyl group. It is named after British chemists Sir Derek Harold Richard Barton and Stuart W. McCombie.

Atom transfer radical polymerization (ATRP) is an example of a reversible-deactivation radical polymerization. Like its counterpart, ATRA, or atom transfer radical addition, ATRP is a means of forming a carbon-carbon bond with a transition metal catalyst. The polymerization from this method is called atom transfer radical addition polymerization (ATRAP). As the name implies, the atom transfer step is crucial in the reaction responsible for uniform polymer chain growth. ATRP was independently discovered by Mitsuo Sawamoto and by Krzysztof Matyjaszewski and Jin-Shan Wang in 1995.

Reversible addition−fragmentation chain-transfer polymerization

Reversible addition−fragmentation chain-transfer or RAFT polymerization is one of several kinds of reversible-deactivation radical polymerization. It makes use of a chain-transfer agent in the form of a thiocarbonylthio compound to afford control over the generated molecular weight and polydispersity during a free-radical polymerization. Discovered at the Commonwealth Scientific and Industrial Research Organisation (CSIRO) of Australia in 1998, RAFT polymerization is one of several living or controlled radical polymerization techniques, others being atom transfer radical polymerization (ATRP) and nitroxide-mediated polymerization (NMP), etc. RAFT polymerization uses thiocarbonylthio compounds, such as dithioesters, thiocarbamates, and xanthates, to mediate the polymerization via a reversible chain-transfer process. As with other controlled radical polymerization techniques, RAFT polymerizations can be performed with conditions to favor low dispersity and a pre-chosen molecular weight. RAFT polymerization can be used to design polymers of complex architectures, such as linear block copolymers, comb-like, star, brush polymers, dendrimers and cross-linked networks.

Radical (chemistry) Atom, molecule, or ion that has an unpaired valence electron; typically highly reactive

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Living free radical polymerization is a type of living polymerization where the active polymer chain end is a free radical. Several methods exist. IUPAC recommends to use the term "reversible-deactivation radical polymerization" instead of "living free radical polymerization", though the two terms are not synonymous.

TEMPO Chemical compound

(2,2,6,6-Tetramethylpiperidin-1-yl)oxyl or (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl, commonly known as TEMPO, is a chemical compound with the formula (CH2)3(CMe2)2NO. This heterocyclic compound is a red-orange, sublimable solid. As a stable aminoxyl radical, it has applications in chemistry and biochemistry. TEMPO is used as a radical marker, as a structural probe for biological systems in conjunction with electron spin resonance spectroscopy, as a reagent in organic synthesis, and as a mediator in controlled radical polymerization.

Radical disproportionation encompasses a group of reactions in organic chemistry in which two radicals react to form two different non-radical products. Radicals in chemistry are defined as reactive atoms or molecules that contain an unpaired electron or electrons in an open shell. The unpaired electrons can cause radicals to be unstable and reactive. Reactions in radical chemistry can generate both radical and non-radical products. Radical disproportionation reactions can occur with many radicals in solution and in the gas phase. Due to the reactive nature of radical molecules, disproportionation proceeds rapidly and requires little to no activation energy. The most thoroughly studied radical disproportionation reactions have been conducted with alkyl radicals, but there are many organic molecules that can exhibit more complex, multi-step disproportionation reactions.

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Graft polymer Polymer with a backbone of one composite and random branches of another composite

In polymer chemistry, graft polymers are segmented copolymers with a linear backbone of one composite and randomly distributed branches of another composite. The picture labeled "graft polymer" shows how grafted chains of species B are covalently bonded to polymer species A. Although the side chains are structurally distinct from the main chain, the individual grafted chains may be homopolymers or copolymers. Graft polymers have been synthesized for many decades and are especially used as impact resistant materials, thermoplastic elastomers, compatibilizers, or emulsifiers for the preparation of stable blends or alloys. One of the better-known examples of a graft polymer is high impact polystyrene, which consists of a polystyrene backbone with polybutadiene grafted chains.

An organic radical battery (ORB) is a type of battery first developed in 2005. As of 2011, this type of battery was generally not available for the consumer, although their development at that time was considered to be approaching practical use. ORBs are potentially more environmentally friendly than conventional metal-based batteries, because they use organic radical polymers to provide electrical power instead of metals. ORBs are considered to be a high-power alternative to the Li-ion battery. Functional prototypes of the battery have been researched and developed by different research groups and corporations including the Japanese corporation NEC.

The thiol-ene reaction is an organic reaction between a thiol and an alkene to form a thioether. This reaction was first reported in 1905, but it gained prominence in the late 1990s and early 2000s for its feasibility and wide range of applications. This reaction is accepted as a click chemistry reaction given the reactions’ high yield, stereoselectivity, high rate, and thermodynamic driving force.

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The persistent radical effect (PRE) in chemistry describes and explains the selective product formation found in certain free-radical cross-reactions. In these type of reactions, different radicals compete in secondary reactions. The so-called persistent (long-lived) radicals do not self-terminate and only react in cross-couplings. In this way, the cross-coupling products in the product distribution are more prominent.

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. Aminoxyls are structurally related to hydroxylamines and N-oxoammonium salts, with which they can interconvert via a series of redox steps.

References

  1. ↑ Nicolas, J., et al. Prog. Polym. Sci., 2013, 38, 63–235
  2. ↑ Moad, G., Rizzardo, E. Macromolecules, 1995, 28, 8722–8728.
  3. ↑ Bertin, D., et al. Chem. Soc. Rev., 2011, 40, 2189–2198
  4. ↑ Fischer, Hanns. Chem. Rev., 2001, 101 (12), 3581–3610.
  5. ↑ Hawker, C.J., Barclay, G.G., Dao, J.J. Am. Chem. Soc., 1996, 118 (46), 11467–11471.
  6. ↑ Volodarsky, L.B., Reznikov, V.A., Ovcharenko, V.I. Synthetic Chemistry of Stable Nitroxides. CRC Press, 1994.
  7. ↑ Bertin, D., et al. Chem. Soc. Rev., 2011, 40, 2189–2198
  8. ↑ Moad, G., Rizzardo, E. Macromolecules, 1995, 28, 8722–8728.
  9. ↑ Siegenthaler, K.O., Studer, A. Macromolecules, 2006, 39(4), 1347–1352.
  10. ↑ Dao, J., Benoit, D., Hawker, C.J.J. Poly. Sci., 1998, 36, 2161–2167.
  11. ↑ Braslo, R., et al. Macromolecules, 1997, 30, 6445–6450.
  12. ↑ Schoening, K.U., et al. J. Org. Chem. 2009, 74, 1567–1573.
  13. ↑ Moon, B., Minjyuk, K. Macromol. Res., 2005, 13(3), 229–235.
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