Community Hub0 Subscribers
Community hub
TEMPO
View on Wikipediafrom Wikipedia
 | |
 | |
| Names | |
|---|---|
| Preferred IUPAC name
(2,2,6,6-Tetramethylpiperidin-1-yl)oxyl | |
| Other names
(2,2,6,6-Tetramethylpiperidin-1-yl)oxidanyl
| |
| Identifiers | |
3D model (JSmol)
|
|
| ChEBI | |
| ChEMBL | |
| ChemSpider | |
| ECHA InfoCard | 100.018.081 |
| EC Number |
|
PubChem CID
|
|
| RTECS number |
|
| UNII | |
CompTox Dashboard (EPA)
|
|
| |
| |
| Properties | |
| C9H18NO | |
| Molar mass | 156.249 g·mol−1 |
| Appearance | Orange-red solid |
| Melting point | 36 to 38 °C (97 to 100 °F; 309 to 311 K) |
| Boiling point | sublimes under vacuum |
| Hazards | |
| GHS labelling: | |
| |
| Danger | |
| H314 | |
| P260, P264, P273, P280, P301+P330+P331, P303+P361+P353, P304+P340, P305+P351+P338, P310, P321, P363, P405, P501 | |
| Safety data sheet (SDS) | External MSDS |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
| |
(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.[1] 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.[2]
Preparation
[edit]TEMPO was discovered by Lebedev and Kazarnowskii in 1960.[3] It is prepared by oxidation of 2,2,6,6-tetramethylpiperidine.[4]
Structure and bonding
[edit]
The structure has been confirmed by X-ray crystallography. The reactive radical is well shielded by the four methyl groups.
The stability of this radical can be attributed to the delocalization of the radical to form a two-center three-electron N–O bond. The stability is reminiscent of the stability of nitric oxide and nitrogen dioxide. Additional stability is attributed to the steric protection provided by the four methyl groups adjacent to the aminoxyl group. These methyl groups serve as inert substituents, whereas any CH center adjacent to the aminoxyl would be subject to abstraction by the aminoxyl.[6]
Regardless of the reasons for the stability of the radical, the O–H bond in the hydrogenated derivative (the hydroxylamine 1-hydroxy-2,2,6,6-tetramethylpiperidine) TEMPO–H is weak. With an O–H bond dissociation energy of about 70 kcal/mol (290 kJ/mol), this bond is about 30% weaker than a typical O–H bond.[7]
Application in organic synthesis
[edit]TEMPO is employed in organic synthesis as a catalyst for the oxidation of primary alcohols to aldehydes. The actual oxidant is the N-oxoammonium salt. In a catalytic cycle with sodium hypochlorite as the stoichiometric oxidant, hypochlorous acid generates the N-oxoammonium salt from TEMPO.
One typical reaction example is the oxidation of (S)-(−)-2-methyl-1-butanol to (S)-(+)-2-methylbutanal:[8] 4-Methoxyphenethyl alcohol is oxidized to the corresponding carboxylic acid in a system of catalytic TEMPO and sodium hypochlorite and a stoichiometric amount of sodium chlorite.[9] TEMPO oxidations also exhibit chemoselectivity, being inert towards secondary alcohols, but the reagent will convert aldehydes to carboxylic acids.
The oxidation of TEMPO can be highly selective. In basic conditions, TEMPO oxidizes primary alcohols before secondary alcohols.[10] But in acid, secondary alcohols provide an H− ion more easily, and oxidize first instead.[11]
In cases where secondary oxidizing agents cause side reactions, it is possible to stoichiometrically convert TEMPO to the oxoammonium salt in a separate step. For example, in the oxidation of geraniol to geranial, 4-acetamido-TEMPO is first oxidized to the oxoammonium tetrafluoroborate.[12]
TEMPO can also be employed in nitroxide-mediated radical polymerization (NMP), a controlled free radical polymerization technique that allows better control over the final molecular weight distribution. The TEMPO free radical can be added to the end of a growing polymer chain, creating a "dormant" chain that stops polymerizing. However, the linkage between the polymer chain and TEMPO is weak, and can be broken upon heating, which then allows the polymerization to continue. Thus, the chemist can control the extent of polymerization and also synthesize narrowly distributed polymer chains.
Industrial applications and analogues
[edit]TEMPO is sufficiently inexpensive for use on a laboratory scale.[13] There is also industrial-scale manufacturer which can provide TEMPO at a reasonable price in large quantity.[14] Structurally related analogues do exist, which are largely based on 4-hydroxy-TEMPO (TEMPOL). This is produced from acetone and ammonia, via triacetone amine, making it much less expensive. Other alternatives include polymer-supported TEMPO catalysts, which are economic due to their recyclability.[15]
Industrial-scale examples of TEMPO-like compounds include hindered amine light stabilizers and polymerisation inhibitors.
See also
[edit]- 1-Hydroxy-2,2,6,6-tetramethylpiperidine, the reduced derivative of TEMPO
- TEMPOL
- Bobbitt's salt
- N-Hydroxyphthalimide
References
[edit]- ^ Barriga, S. (2001). "2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO)" (PDF). Synlett. 2001 (4): 563. doi:10.1055/s-2001-12332.
- ^ Montanari, F.; Quici, S.; Henry-Riyad, H.; Tidwell, T. T. (2005). "2,2,6,6-Tetramethylpiperidin-1-oxyl". Encyclopedia of Reagents for Organic Synthesis. John Wiley & Sons. doi:10.1002/047084289X.rt069.pub2. ISBN 0471936235.
- ^ Lebedev, O. L.; Kazarnovskii, S. N. (1960). "[Catalytic oxidation of aliphatic amines with hydrogen peroxide]". Zhur. Obshch. Khim. 30 (5): 1631–1635. CAN 55:7792.
- ^ Mahapatro, Surendra N.; Kallan, Nicholas C.; Hovey, Tanden A.; De Dios, Robyn Krystal; Vergil, Catherine; Lai, Trinh; De Dios, Robert Christian; Tran, Danny; McEvoy, James P. (2024). "TEMPO Synthesis, Characterization and Catalysis: An Integrated Upper-Division Laboratory". Journal of Chemical Education. 101 (12): 5449–5459. Bibcode:2024JChEd.101.5449M. doi:10.1021/acs.jchemed.4c00739.
- ^ Yonekuta Yasunori, Oyaizu Kenichi, Nishide Hiroyuki (2007). "Structural Implication of Oxoammonium Cations for Reversible Organic One-electron Redox Reaction to Nitroxide Radicals". Chem. Lett. 36 (7): 866–867. doi:10.1246/cl.2007.866.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Zanocco, A. L.; Canetem, A. Y.; Melendez, M. X. (2000). "A Kinetic Study of the Reaction between 2-p-methoxyphenyl-4-phenyl-2-oxazolin-5-one and 2,2,6,6-Tetramethyl-1-piperidinyl-N-oxide". Boletín de la Sociedad Chilena de Química. 45 (1): 123–129. doi:10.4067/S0366-16442000000100016.
- ^ Galli, C. (2009). "Nitroxyl radicals". Chemistry of Hydroxylamines, Oximes and Hydroxamic Acids. Vol. 2. John Wiley & Sons. pp. 705–750. ISBN 978-0-470-51261-6. LCCN 2008046989.
- ^ Anelli, P. L.; Montanari, F.; Quici, S. (1990). "A General Synthetic Method for the Oxidation of Primary Alcohols to Aldehydes: (S)-(+)-2-Methylbutanal". Organic Syntheses. 69: 212
{{cite journal}}: CS1 maint: multiple names: authors list (link); Collected Volumes, vol. 8, p. 367. - ^ Zhao, M. M.; Li, J.; Mano, E.; Song, Z. J.; Tschaen, D. M. (2005). "Oxidation of Primary Alcohols to Carboxylic Acids with Sodium Chlorite catalyzed by TEMPO and Bleach: 4-Methoxyphenylacetic Acid". Organic Syntheses. 81: 195
{{cite journal}}: CS1 maint: multiple names: authors list (link). - ^ de Nooy, Arjan E.J.; Besemer, Arie C.; van Bekkum, Herman (July 1995). "Selective oxidation of primary alcohols mediated by nitroxyl radical in aqueous solution. Kinetics and mechanism". Tetrahedron. 51 (29): 8023–8032. doi:10.1016/0040-4020(95)00417-7.
- ^ "Detailed study about TEMPO oxidation". LISKON-CHEM.
- ^ Bobbitt, J. M.; Merbouh, N. (2005). "2,6-Octadienal, 3,7-dimethyl-, (2E)-". Organic Syntheses. 82: 80
{{cite journal}}: CS1 maint: multiple names: authors list (link). - ^ "TEMPO". Sigma-Aldrich.
- ^ "TEMPO-LISKON industrial-scale".
- ^ Ciriminna, R.; Pagliaro, M. (2010). "Industrial Oxidations with Organocatalyst TEMPO and Its Derivatives". Organic Process Research & Development. 14 (1): 245–251. doi:10.1021/op900059x.
External links
[edit]TEMPO
View on Grokipediafrom Grokipedia
Physical properties
Appearance and phase behavior
TEMPO, or 2,2,6,6-tetramethylpiperidine-1-oxyl, appears as a red-orange crystalline solid at room temperature.[5] This characteristic color arises from its stable nitroxyl radical structure, and the compound has an amine-like odor.[5] With a molecular weight of 156.25 g/mol, TEMPO exhibits low volatility under ambient conditions. The melting point of TEMPO is 36–38 °C, allowing it to transition to a liquid state near room temperature depending on purity and conditions. It sublimes readily under vacuum, which is commonly employed for purification, and no distinct boiling point is reported due to this sublimation behavior and potential decomposition at higher temperatures.[6][7] This phase behavior makes TEMPO suitable for handling as a solid in laboratory settings while facilitating clean sublimation for removal or isolation in synthetic processes.Solubility and stability
TEMPO displays excellent solubility in a range of organic solvents, including dichloromethane, acetone, and ethanol, where concentrations exceeding 100 g/L can be achieved at room temperature, facilitating its use in non-aqueous reaction media.[8] In contrast, its solubility in water is significantly lower, typically around 9–12 g/L, which limits direct applications in purely aqueous systems without modifications or cosolvents.[6][9] The compound exhibits remarkable stability under ambient conditions, remaining intact in air at room temperature for years without appreciable degradation, owing to its inherent chemical robustness as a nitroxide radical.[10] Thermal decomposition begins above 150 °C, leading to the formation of 2,2,6,6-tetramethylpiperidine as a primary product along with minor byproducts such as hydroxylamine derivatives.[11][12] TEMPO's resistance to dimerization, a common decay pathway for radicals, arises from steric hindrance imposed by the four geminal methyl groups flanking the nitroxide moiety, which effectively shields the reactive nitrogen-oxygen center and prevents intermolecular coupling.[13] This structural feature contributes to its long half-life in solution under aerobic conditions, often exceeding several months, enabling prolonged storage and use in catalytic applications.[14] The protonated form of the oxoammonium ion derived from TEMPO oxidation has a pKa of approximately 0, indicating weak basicity and influencing its behavior in acidic environments where protonation is minimal.[15]Structure and bonding
Molecular geometry
TEMPO exhibits a chair conformation in its piperidine ring, akin to cyclohexane, with the four methyl groups at positions 2 and 6 occupying equatorial positions to minimize steric strain. This arrangement imparts substantial steric bulk around the nitroxide moiety, effectively shielding the radical center and restricting intermolecular interactions.[16] The N–O bond measures approximately 1.28 Å, longer than a standard N–O single bond owing to partial double-bond character from radical delocalization. The C–N–O angle at the nitrogen atom reflects the pyramidal geometry typical of aminoxyl radicals.[16] The structure has been confirmed by X-ray crystallography.Electronic structure and radical nature
TEMPO exhibits a stable unpaired electron delocalized over the N–O π-system of its nitroxide functional group, with spin density distributed primarily on the oxygen (approximately 65%) and nitrogen (approximately 25%) atoms.[17] This delocalization arises from the π-conjugation between the nitrogen lone pair and the oxygen p-orbital, contributing to the radical's persistence under ambient conditions.[17] The radical character is further characterized by two key resonance structures: , where the unpaired electron is formally located on either the oxygen or nitrogen atom, with corresponding charge separation.[18] This resonance stabilization, combined with the cyclic piperidine framework, enhances the overall electronic stability of the species. Electron paramagnetic resonance (EPR) spectroscopy confirms the electronic structure, revealing a nitrogen hyperfine coupling constant of G and a smaller coupling to the methyl protons of G, indicative of the delocalized spin and limited interaction with remote hydrogens.[19] The gem-dimethyl groups at the 2 and 6 positions provide steric protection to the nitroxide moiety, minimizing radical-radical coupling and dimerization reactions that could otherwise destabilize the species.[20] This structural feature imparts the characteristic red color to TEMPO, resulting from an n–π* electronic transition with absorption maximum near 436 nm in the visible region.[21]Preparation
Laboratory synthesis
TEMPO was first synthesized in 1960 by Lebedev and Kazarnovskii through the oxidation of 2,2,6,6-tetramethylpiperidine (TMP). A primary laboratory method for its preparation involves the oxidation of TMP with 30% hydrogen peroxide in the presence of sodium tungstate dihydrate as catalyst at 0–5 °C, providing TEMPO in yields greater than 90%.[22] This approach leverages the activation of hydrogen peroxide by the tungstate catalyst to effect the three-electron oxidation required to form the stable nitroxide radical. The reaction is typically conducted in an aqueous or mixed solvent system under controlled temperature to minimize over-oxidation or side products. Following synthesis, TEMPO is purified by sublimation under reduced pressure or recrystallization from pentane to obtain the red-orange crystalline solid.[23] The overall transformation is represented by the equation:Commercial production
TEMPO is commercially produced via the selective oxidation of 2,2,6,6-tetramethylpiperidine (TMP) using hydrogen peroxide in the presence of a tungstate catalyst, such as sodium tungstate dihydrate, which activates the oxidant for efficient three-electron transfer to form the nitroxide radical. This process, often conducted in aqueous or mixed-solvent media, can be scaled using continuous flow reactors to enhance yield, safety, and throughput while minimizing waste. Economic considerations favor this method due to the low cost and availability of hydrogen peroxide as the primary oxidant, with catalyst loadings typically below 1 mol% to optimize efficiency. Major suppliers including Sigma-Aldrich (now part of MilliporeSigma) and Tokyo Chemical Industry Co., Ltd. (TCI) have manufactured and distributed TEMPO since the 1980s, initially for research purposes and later expanding to support industrial catalysis demands. These companies maintain high-volume production capabilities, with global output estimated in the tons-per-year range to meet growing needs in fine chemicals and polymer industries. In bulk quantities (e.g., kilograms), TEMPO costs approximately $0.3–1 per gram, varying by purity grade and order volume, which supports its viability for large-scale applications without prohibitive expenses. Quality assurance in commercial production relies on electron paramagnetic resonance (EPR) spectroscopy to quantify the unpaired electron content, confirming radical purity exceeding 98% and distinguishing the active nitroxide from hydroxylamine byproducts.Applications in organic synthesis
Oxidation catalysis
TEMPO serves as a highly effective catalyst for the selective oxidation of alcohols to carbonyl compounds, particularly primary alcohols to aldehydes, through the generation of an active oxoammonium species. One of the most widely adopted methods is the Anelli oxidation, which employs catalytic TEMPO (typically 1-2 mol%) in a biphasic dichloromethane/water system with sodium hypochlorite (NaOCl) as the terminal oxidant and potassium bromide (KBr) as a co-catalyst. This process operates at room temperature or slightly below (0-25°C) and maintains a pH of 8-10 using a bicarbonate buffer, enabling high selectivity (>95%) for aldehyde formation from primary alcohols while avoiding over-oxidation to carboxylic acids under anhydrous organic phase conditions. Turnover numbers often exceed 1000, making it efficient for laboratory-scale syntheses of sensitive substrates like allylic or benzylic alcohols.[24][25] An alternative approach involves TEMPO in combination with copper catalysts for aerobic oxidations using air or molecular oxygen as the stoichiometric oxidant, particularly suited for benzylic alcohols. In these systems, such as the Semmelhack protocol using CuCl (5-10 mol%) and TEMPO in acetonitrile or DMF at ambient temperature, primary benzylic alcohols are converted to aldehydes with good yields (70-90%) and minimal over-oxidation. Modern variants, like the (bipyridine)CuI/TEMPO system, enhance efficiency and substrate scope, including aliphatic alcohols, under mild conditions (room temperature, 1 atm air) with catalyst loadings as low as 1 mol%, achieving turnover numbers up to several thousand. These copper-mediated methods are valued for their environmental benefits, avoiding halogen-based oxidants.[26] The underlying mechanism across these systems involves the one-electron oxidation of TEMPO by the co-oxidant (e.g., NaOCl or CuII species) to form the electrophilic oxoammonium cation (TEMPO⁺), which then reacts with the alcohol substrate. This proceeds via nucleophilic addition of the alcohol to TEMPO⁺, forming a hemiketal-like intermediate that eliminates to yield the carbonyl product and the hydroxylamine (TEMPO–H). The hydroxylamine is subsequently reoxidized to TEMPO, closing the catalytic cycle. For primary alcohols, selectivity toward aldehydes is controlled by pH and phase separation, which limits aldehyde hydration and further oxidation; inclusion of water or a phase-transfer catalyst promotes hydration and oxidation to carboxylic acids. A representative equation for the key step is:
This mechanism ensures mild conditions compatible with acid-sensitive functional groups.[27]
Other roles in reactions
TEMPO serves as a radical trap in free radical polymerization processes, where it inhibits unwanted radical reactions by rapidly reacting with carbon-centered radicals to form stable adducts, thereby terminating chain propagation and preventing premature polymerization. This property is particularly valuable in the formulation of acrylic paints and adhesives, which rely on monomers like acrylic acid and methyl methacrylate; TEMPO's addition stabilizes these systems during storage and processing by suppressing autopolymerization induced by heat, light, or impurities.[28] In living radical polymerization techniques such as nitroxide-mediated polymerization (NMP), TEMPO functions as a capping agent that enables precise control over polymer chain growth. The mechanism involves the reversible trapping of growing polymer radicals by TEMPO to form dormant alkoxyamine species, which dissociate under thermal activation to regenerate the radical and nitroxide; this equilibrium maintains low radical concentrations, minimizing termination events and yielding polymers with narrow polydispersity indices and targeted molecular weights, especially for styrenes and acrylates.[29] TEMPO and its derivatives are employed as spin labels in biochemical electron paramagnetic resonance (EPR) spectroscopy to probe protein dynamics and conformational changes. By covalently attaching TEMPO to specific amino acid residues, researchers can monitor rotational mobility and environmental interactions through variations in the EPR spectrum's hyperfine splitting and linewidth, providing insights into protein folding, binding events, and local polarity without disrupting native structure.[30] As a mediator in C–H functionalization reactions, TEMPO facilitates the selective activation of unactivated alkane C–H bonds when paired with visible-light photocatalysts, acting as a hydrogen atom transfer (HAT) agent to generate alkyl radicals that undergo subsequent oxidation under aerobic conditions. This approach enables mild, metal-free or cooperative photocatalytic transformations of alkanes into functionalized products, leveraging TEMPO's redox cycling to abstract hydrogen and propagate radical intermediates efficiently.[31] A notable example of TEMPO's role in non-alcohol oxidations is its use in the aerobic conversion of primary amines to imines, often with iron co-catalysts like Fe(NO3)3, where TEMPO promotes radical-mediated dehydrogenation under ambient oxygen to afford high yields of imines as key synthetic intermediates.[32]Industrial applications and analogues
Uses in materials and processes
In the pulp and paper industry, TEMPO functions as a co-catalyst alongside laccase enzymes to facilitate eco-friendly delignification of wood pulp. This laccase-mediator system selectively oxidizes lignin components, reducing the need for harsh chemical bleaches and promoting sustainable bleaching processes that minimize environmental discharge. Studies have shown TEMPO and its derivatives, such as 4-hydroxy-TEMPO, to be among the most efficient mediators for enhancing laccase activity in kraft pulp treatments.[33] TEMPO also plays a key role in battery electrolytes as a redox mediator in organic flow batteries, particularly non-aqueous and aqueous variants for large-scale energy storage. Its reversible one-electron oxidation at approximately 0.7–1.0 V vs. SHE enables efficient charge transfer and high solubility, contributing to stable cycling performance in systems like TEMPO-based catholytes paired with viologen anolytes. Recent advancements have focused on derivatives to mitigate crossover issues, enhancing overall battery efficiency and lifespan.[34][35] Regarding environmental considerations, TEMPO demonstrates low acute toxicity in dilute formulations used industrially, with no observed adverse effects in aquatic organisms at relevant exposure levels.[36][37]Related compounds
4-Hydroxy-TEMPO, commonly known as TEMPOL, is a derivative of TEMPO featuring a hydroxyl group at the 4-position of the piperidine ring, which enhances its water solubility compared to the parent compound while maintaining the characteristic stability of the nitroxide radical.[38] This increased solubility, reported to be significantly higher than that of TEMPO (e.g., TEMPOL is soluble up to at least 0.5 M in aqueous media under typical conditions), facilitates its application in biological environments.[39] TEMPOL acts as a redox-cycling agent that scavenges reactive oxygen species (ROS) and improves nitric oxide bioavailability, making it particularly useful in biomedical contexts for radical scavenging and as a potential radioprotector during cancer therapies.[40] 4-Amino-TEMPO, bearing an amino group at the 4-position, exhibits higher reactivity than TEMPO due to the nucleophilic nature of the amine, which enables facile attachment to biomolecules via covalent bonding.[41] This derivative is widely employed in spin labeling techniques for electron paramagnetic resonance (EPR) spectroscopy, where it probes conformational changes and distances in proteins and nucleic acids by integrating the stable nitroxide radical into specific sites.[42] Its reactivity allows for site-specific labeling of cysteine residues or other functional groups, enhancing resolution in structural biology studies.[43] PROXYL derivatives, such as 2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole-1-oxyl, feature a five-membered pyrrolidine ring in place of TEMPO's six-membered piperidine, resulting in less steric hindrance around the N-O group and consequently faster reaction rates in certain catalytic and scavenging processes.[44] These analogues demonstrate superior stability against reduction compared to many other nitroxides, attributed to the ring structure, and are preferred for EPR probes in biological systems due to their smaller size and ability to report on local environments with minimal perturbation.[45] Di-TEMPO, often in the form of biscationic or ionic derivatives (e.g., with quaternary ammonium groups), incorporates two TEMPO units linked by a spacer, conferring amphiphilic properties that enable phase-transfer catalysis in biphasic oxidation reactions.[46] These versions improve solubility in aqueous-organic interfaces, allowing efficient transfer of oxidants like hypochlorite for alcohol oxidations while recycling the catalyst.[47]| Compound | Stability | Solubility | Primary Application |
|---|---|---|---|
| TEMPO | High (sterically protected nitroxide) | Low in water; good in organic solvents | Oxidation catalysis in synthesis |
| 4-Hydroxy-TEMPO (TEMPOL) | High, similar to TEMPO | High in water (e.g., >0.5 M) | Biomedical radical scavenging |
| 4-Amino-TEMPO | Moderate to high | Moderate in water | Spin labeling in EPR spectroscopy |
| PROXYL derivatives | Highest against reduction | Variable, often higher in polar media | EPR probes and faster scavenging |
| Di-TEMPO (biscationic) | High | Enhanced at phase interfaces | Phase-transfer oxidation catalysis |