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Balz–Schiemann reaction
View on Wikipediafrom Wikipedia
| Balz-Schiemann reaction | |
|---|---|
| Named after | Günther Balz Günther Schiemann |
| Reaction type | Substitution reaction |
| Identifiers | |
| Organic Chemistry Portal | balz-schiemann-reaction |
| RSC ontology ID | RXNO:0000127 |
The Balz–Schiemann reaction (also called the Schiemann reaction) is a chemical reaction in which a primary aromatic amine is transformed to an aryl fluoride via a diazonium tetrafluoroborate intermediate.[1][2][3] This reaction is a traditional route to fluorobenzene and some related derivatives,[4] including 4-fluorobenzoic acid.[5]
The reaction is conceptually similar to the Sandmeyer reaction, which converts diazonium salts to other aryl halides (ArCl, ArBr).[6] However, while the Sandmeyer reaction involves a copper reagent/catalyst and radical intermediates,[7] the thermal decomposition of the diazonium tetrafluoroborate proceeds without a promoter and is believed to generate highly unstable aryl cations (Ar+), which abstract F− from BF4− to give the fluoroarene (ArF), along with boron trifluoride and nitrogen as the byproducts.
Innovations
[edit]The traditional Balz–Schiemann reaction employs HBF4 and involves isolation of the diazonium salt. Both aspects can be profitably modified. Other counterions have been used in place of tetrafluoroborates, such as hexafluorophosphates (PF6−) and hexafluoroantimonates (SbF6−) with improved yields for some substrates.[8][9] The diazotization reaction can be effected with nitrosonium salts such as [NO]SbF6 without isolation of the diazonium intermediate.[2]
As a practical matter, the traditional Balz–Schiemann reaction consumes relatively expensive BF4− as a source of fluoride. An alternative methodology produces the fluoride salt of the diazonium compound. In this implementation, the diazotization is conducted with a solution of sodium nitrite in liquid hydrogen fluoride:[10]
- ArNH2 + 2 HF + NaNO2 → [ArN2]F + NaF + 2 H2O
- [ArN2]F → ArF + N2
History
[edit]The reaction is named after the German chemists Günther Schiemann and Günther Balz.[1]
Examples
[edit]4-Fluorotoluene is made in ~89% yield by Balz–Schiemann reaction on p-toluidine.[11] This is then used as a precursor for 4-fluorobenzaldehyde,[12]
Balz–Schiemann reaction is used in the synthesis of DOF & 2C-F. The starting material for the first step in the synthesis is called 2,5-dimethoxyaniline [102-56-7].
The Balz–Schiemann reaction is used in the synthesis of Fipamezole from Atipamezole.[13]
Additional literature
[edit]- Roe A (1949). "Preparation of Aromatic Fluorine Compounds from Diazonium Fluoborates". Org. React. 5: 193. doi:10.1002/0471264180.or005.04. ISBN 0471264180.
{{cite journal}}: ISBN / Date incompatibility (help) - Becker H. G. O., Israel G. (1978). "Ionenpaareffekte bei der Photolyse und Thermolyse von Aryldiazonium-tetrafluoroboraten". J. Prakt. Chem. 321 (4): 579–586. doi:10.1002/prac.19793210410.
References
[edit]- ^ a b Balz, Günther; Schiemann, Günther (1927). "Über aromatische Fluorverbindungen, I.: Ein neues Verfahren zu ihrer Darstellung" [Aromatic fluorine compounds. I. A new method for their preparation.]. Chemische Berichte (in German). 60 (5): 1186–1190. doi:10.1002/cber.19270600539.
- ^ a b Furuya, Takeru; Klein, Johannes E. M. N.; Ritter, Tobias (2010). "C–F Bond Formation for the Synthesis of Aryl Fluorides". Synthesis. 2010 (11): 1804–1821. doi:10.1055/s-0029-1218742. PMC 2953275. PMID 20953341.
- ^ Carey, Francis A.; Sundberg, Richard J. (2007). Advanced Organic Chemistry: Part B: Reactions and Synthesis (5th ed.). New York: Springer. p. 1031. ISBN 978-0387683546.
- ^ Flood, D. T. (1943). "Fluorobenzene". Organic Syntheses; Collected Volumes, vol. 2, p. 295.
- ^ G. Schiemann; W. Winkelmüller (1943). "p-Fluorobenzoic Acid". Organic Syntheses; Collected Volumes, vol. 2, p. 299.
- ^ Swain, C. G.; Rogers, R. J. (1975). "Mechanism of formation of aryl fluorides from arenediazonium fluoborates". J. Am. Chem. Soc. 97 (4): 799–800. Bibcode:1975JAChS..97..799S. doi:10.1021/ja00837a019.
- ^ Carey, Francis A.; Sundberg, Richard J. (2007). Advanced Organic Chemistry: Part B: Reactions and Synthesis (5th ed.). New York: Springer. pp. 1030–1031. ISBN 978-0387683546.
- ^ Rutherford, Kenneth G.; Redmond, William; Rigamonti, James (1961). "The Use of Hexafluorophosphoric Acid in the Schiemann Reaction". The Journal of Organic Chemistry. 26 (12): 5149–5152. doi:10.1021/jo01070a089.
- ^ Sellers, C.; Suschitzky, H. (1968). "The use of arenediazonium hexafluoro-antimonates and -arsenates in the preparation of aryl fluorides". Journal of the Chemical Society C: Organic: 2317–2319. doi:10.1039/J39680002317.
- ^ Siegemund, Günter; Schwertfeger, Werner; Feiring, Andrew; Smart, Bruce; Behr, Fred; Vogel, Herward; McKusick, Blaine (2000). "Fluorine Compounds, Organic". Ullmann's Encyclopedia of Industrial Chemistry. doi:10.1002/14356007.a11_349. ISBN 3527306730.
- ^ Yu, Z., Lv, Y., Yu, C., Su, W. (March 2013). "Continuous flow reactor for Balz–Schiemann reaction: a new procedure for the preparation of aromatic fluorides". Tetrahedron Letters. 54 (10): 1261–1263. doi:10.1016/j.tetlet.2012.12.084.
- ^ Laali, K. K., Herbert, M., Cushnyr, B., Bhatt, A., Terrano, D. (2001). "Benzylic oxidation of aromatics with cerium(IV) triflate; synthetic scope and mechanistic insight". Journal of the Chemical Society, Perkin Transactions 1 (6): 578–583. doi:10.1039/b008843i.
- ^ Arto Johannes Karjalainen, et al. WO1993013074 (to Orion Oyj).
Balz–Schiemann reaction
View on Grokipediafrom Grokipedia
The Balz–Schiemann reaction is a classical method in organic chemistry for introducing a fluorine atom into aromatic rings by converting primary aromatic amines into the corresponding aryl fluorides. This transformation proceeds via diazotization of the amine with nitrous acid in the presence of fluoroboric acid to form a diazonium tetrafluoroborate salt, followed by thermal decomposition of this intermediate to yield the fluorinated product, often with nitrogen gas as a byproduct.[1][2]
First reported in 1927 by German chemists Günther Balz and Günther Schiemann, the reaction marked a significant advancement in aromatic fluorination at a time when direct fluorination methods were limited and hazardous.[3] The process has been extensively reviewed since its discovery, with early optimizations focusing on solvent-free decompositions to achieve good yields for both electron-rich and electron-poor substrates. Mechanistically, the reaction involves the generation of an aryl diazonium cation (ArN₂⁺), which undergoes heterolytic cleavage upon heating to form a short-lived aryl cation intermediate; this electrophile is then trapped by fluoride ion from the tetrafluoroborate counterion in an Sₙ1-type process, though the exact pathway remains somewhat obscure due to the instability of intermediates.[4][2]
While effective for regioselective fluorination with tolerance for various functional groups, the traditional Balz–Schiemann reaction suffers from limitations such as the need for high temperatures (typically 100–200 °C), exothermic decompositions that pose explosion risks, and variable salt stability, particularly for ortho- or meta-substituted derivatives.[4] Modern adaptations have addressed these challenges through photochemical initiation under visible light, the use of ionic liquids as solvents, non-polar media to achieve yields up to 97%, and continuous-flow setups for safe, scalable production, including kilogram quantities of difluorobenzenes.[2][5]
The reaction's utility extends to the synthesis of fluorinated building blocks in pharmaceuticals, agrochemicals, and materials science, as well as radiolabeled aryl fluorides (e.g., with ¹⁸F) for positron emission tomography imaging, where it provides high regioselectivity despite modest radiochemical yields of 2–15% in some cases.[4][5]
[7]
Introduction
Reaction Overview
The Balz–Schiemann reaction is a classical method in organic chemistry for the conversion of primary aromatic amines to aryl fluorides through the formation and decomposition of diazonium tetrafluoroborate intermediates.[6] This process provides a direct route to introduce fluorine onto aromatic rings, addressing the challenges associated with direct fluorination due to fluorine's high reactivity.[7] It functions analogously to the Sandmeyer reaction, which replaces the diazonium group with other halides using copper catalysis, but the Balz–Schiemann variant is tailored specifically for fluoride incorporation via the stable tetrafluoroborate salt.[4] The reaction necessitates primary aromatic amines that can undergo diazotization under acidic conditions to form the requisite diazonium species.[1] The significance of the Balz–Schiemann reaction lies in its utility for synthesizing aryl fluorides, which are essential building blocks in pharmaceuticals and advanced materials.[8] Fluorine's incorporation enhances molecular properties such as metabolic stability and lipophilicity, making these compounds valuable for drug design and agrochemical applications.[9]General Scheme
The Balz–Schiemann reaction proceeds via a two-stage process to convert an arylamine into the corresponding aryl fluoride. In the first stage, diazotization of the arylamine occurs in the presence of nitrous acid and fluoroboric acid, yielding the aryl diazonium tetrafluoroborate salt as a precipitable intermediate. The second stage involves thermal decomposition of this dried salt to afford the aryl fluoride product.[10] The overall transformation is summarized by the following equations: where Ar represents an aryl group.[2] Diazotization is typically conducted at 0–5 °C to ensure controlled formation and precipitation of the diazonium salt, which is then isolated by filtration and dried under vacuum. Thermal decomposition follows at 100–200 °C, often in an inert solvent such as chlorobenzene or hexane, to facilitate the reaction while minimizing side products.[10][11] This scheme illustrates the process as a linear sequence: starting from the arylamine substrate, proceeding through the stable diazonium tetrafluoroborate intermediate, and culminating in the fluoroarene upon heating, with no additional catalysts required under standard conditions.[2] Byproducts of the decomposition include nitrogen gas (N₂), which evolves quantitatively and requires venting in a fume hood, and boron trifluoride (BF₃), a reactive gas that is typically managed by conducting the reaction in a solvent to dissolve or trap it and prevent equipment corrosion.[2]Historical Development
Discovery
The Balz–Schiemann reaction was discovered in 1927 by the German chemists Günther Balz and Günther Schiemann, affiliated with the Institute of Organic Chemistry and the Institute of Inorganic Chemistry at the Technical University of Hannover.[3] Their work addressed the longstanding challenge of synthesizing aromatic fluorides, as prior methods involving direct fluorination with elemental fluorine were extremely hazardous due to the element's high reactivity and tendency to cause violent explosions.[6] Balz and Schiemann sought to develop a milder, more controlled approach leveraging diazonium chemistry to selectively introduce fluorine.[3] The initial report, published in Chemische Berichte, detailed the conversion of aniline to fluorobenzene as a prototypical example.[3] The process involved diazotization of the amine, precipitation of the diazonium tetrafluoroborate salt using fluoroboric acid, and thermal decomposition of the dry salt to yield the aryl fluoride, along with nitrogen and boron trifluoride.[3] In this seminal work, the yield of fluorobenzene was reported to be approximately 70%, reflecting the method's feasibility despite challenges such as salt stability and side reactions during decomposition.[3] This efficiency established the reaction as a practical alternative for fluorine incorporation.[5]Subsequent Advancements
Following the initial discovery, refinements to the Balz–Schiemann reaction in the 1930s and 1940s focused on optimizing the preparation and handling of diazonium tetrafluoroborates to improve their stability and decomposition yields. Arthur Roe detailed procedures for isolating these salts as dry, crystalline solids by conducting diazotization in aqueous fluoroboric acid at low temperatures (0–5°C), followed by precipitation with ethanol or ether and vacuum drying, which minimized hydrolysis and enhanced thermal stability during storage.[12] These techniques addressed early challenges with salt purity, achieving overall yields of 50–80% for simple aryl fluorides like fluorobenzene from aniline.[12] In the late 1940s, the reaction was extended to heteroaromatic systems, particularly pyridine derivatives, demonstrating its versatility beyond carbocycles. Roe and co-workers applied the refined isolation protocol to 2-, 3-, and 4-aminopyridines, yielding the corresponding monofluoropyridines through thermal decomposition of the isolated diazonium salts at 150–200°C in a sand bath, with reported yields of 70% for 2-fluoropyridine, 60% for 3-fluoropyridine, and 65% for 4-fluoropyridine.[13] This expansion highlighted the method's applicability to electron-deficient rings, though lower yields were noted for more complex heterocycles due to competing side reactions like reduction to hydrazines.[13] Modifications involving alternative fluoride sources, such as hexafluorophosphate anions, were introduced in the 1960s to boost decomposition efficiency and improve yields.[4] During the 1960s and 1970s, the Balz–Schiemann reaction gained traction in industrial synthesis for producing fluorinated aromatic intermediates. Roe's 1949 review served as a foundational reference for these applications, emphasizing the reaction's role in accessing fluorinated building blocks essential for commercial organofluorine production.[12] Early safety protocols emerged in the 1950s in response to the recognized explosive hazards of dry diazonium tetrafluoroborates, particularly during heating. Roe recommended controlled thermal decomposition using gradual heating in an inert medium like xylene or sand (starting at 100°C and ramping to 200°C over 30–60 minutes) to prevent rapid gas evolution and detonation, along with small-scale isolation to limit shock sensitivity.[12] These measures, informed by incidents of spontaneous explosions in impure salts, significantly reduced risks and enabled safer laboratory and early industrial handling through the 1980s.[12]Reaction Mechanism
Diazotization
The diazotization step in the Balz–Schiemann reaction involves the conversion of a primary aromatic amine (ArNH₂) to the corresponding aryldiazonium chloride salt (ArN₂⁺ Cl⁻), serving as the initial phase toward aryl fluorination.[14] This process occurs through the reaction of the amine with nitrous acid (HNO₂), which is generated in situ from sodium nitrite (NaNO₂) and hydrochloric acid (HCl).[15] The overall transformation can be represented by the equation: where Ar denotes an aryl group.[14] The reaction proceeds via electrophilic attack of the nitrosonium ion (NO⁺), formed from protonation and dehydration of HNO₂, on the amine nitrogen, followed by proton transfers and loss of water to yield the diazonium ion.[15] Key factors ensuring successful diazotization include maintaining low temperatures of 0–5°C to minimize premature decomposition of the unstable diazonium intermediate, as higher temperatures promote side reactions or loss of nitrogen gas.[14] The in situ generation of HNO₂ is critical, as it provides a controlled supply of the nitrosating agent under acidic conditions, preventing excess nitrous acid that could lead to unwanted byproducts.[15] Aryldiazonium chlorides exhibit limited stability and are prone to explosive decomposition, particularly in the solid state, due to their sensitivity to shock and heat; thus, they are not isolated prior to anion exchange for fluorination but are instead used directly in solution.[5][15] This instability underscores the need for immediate conversion to more robust salts in the Balz–Schiemann process, originally developed by Balz and Schiemann in 1927.Diazonium Salt Formation
Following the diazotization of an aromatic amine to form the initial aryldiazonium chloride salt, the next step in the Balz–Schiemann reaction involves an anion metathesis to exchange the chloride counterion for tetrafluoroborate (BF₄⁻). Alternatively, direct diazotization can be performed using sodium nitrite in fluoroboric acid, forming the tetrafluoroborate salt without intermediate chloride. This is achieved by treating the aryldiazonium chloride solution (ArN₂⁺ Cl⁻) with fluoroboric acid (HBF₄), resulting in the formation of the aryldiazonium tetrafluoroborate salt according to the equation: This exchange reaction occurs under controlled low-temperature conditions, typically around 0–5 °C, to maintain the integrity of the diazonium cation. The aryldiazonium tetrafluoroborate salt precipitates directly from the reaction mixture as a sparingly soluble white solid, facilitating its straightforward isolation by filtration. This precipitation is driven by the low solubility of the BF₄⁻ salt in aqueous media, allowing for efficient separation from the byproduct HCl and excess reagents. The isolated solid can be washed and dried under reduced pressure, yielding a stable intermediate suitable for storage and subsequent decomposition. The tetrafluoroborate anion imparts enhanced thermal stability to the diazonium salt compared to the chloride counterpart, with many derivatives remaining intact up to approximately 100 °C, though careful handling is required to avoid unintended decomposition. This stability arises from the weakly coordinating nature of BF₄⁻, which better shields the reactive cation and minimizes side reactions such as hydrolysis or reduction. Additionally, the BF₄⁻ serves as an internal fluoride source during the later decomposition step, promoting clean aryl fluoride formation while generating BF₃ as a byproduct. The use of BF₄⁻ over Cl⁻ is thus essential for both isolating a handleable intermediate and optimizing the overall fluorination efficiency.Decomposition Step
The decomposition step of the Balz–Schiemann reaction involves the thermal activation of the preformed aryldiazonium tetrafluoroborate salt, [ArN₂]BF₄, often heated to temperatures between 100 and 200 °C in traditional procedures, though modern solvent-based methods can employ lower temperatures (50–100 °C).[2] This process initiates the loss of nitrogen gas (N₂), generating a short-lived aryl cation intermediate (Ar⁺) through heterolytic cleavage of the carbon-nitrogen bond.[16] The aryl cation then rapidly recombines with a fluoride ion (F⁻) derived from the tetrafluoroborate counterion (BF₄⁻), yielding the desired aryl fluoride (ArF).[6] The overall transformation can be represented by the following equation: This equation highlights the clean release of N₂ and the formation of boron trifluoride (BF₃) as a byproduct. The heterolytic mechanism is supported by extensive experimental evidence, including the observation of rearrangement products and nucleophilic capture by solvents or additives, which are characteristic of free or ion-paired aryl cations.[16] Isotope labeling studies on analogous thermal decompositions of aryldiazonium salts have further confirmed the involvement of discrete cationic intermediates, demonstrating reversible bond breaking and migration patterns inconsistent with concerted pathways.[17] In the Balz–Schiemann context, the tetrafluoroborate anion serves dually as a stabilizing counterion during salt isolation and a fluoride source during decomposition, minimizing side reactions by providing a non-nucleophilic environment until activation.[2] The BF₃ byproduct is released as a gas and can pose handling challenges due to its reactivity; in practice, it is often scavenged by the addition of water, which hydrolyzes BF₃ to boric acid and hydrogen fluoride.[1] This step ensures the reaction proceeds efficiently while capturing volatile byproducts, though care must be taken to avoid excess moisture that could destabilize the diazonium salt prematurely.[6]Synthetic Procedure
Preparation of Intermediates
The preparation of the diazonium tetrafluoroborate intermediate in the Balz–Schiemann reaction involves two key stages: diazotization of the primary aromatic amine to form the diazonium chloride, followed by anion exchange with tetrafluoroboric acid to precipitate the stable tetrafluoroborate salt. This intermediate is essential for the subsequent fluorination step and must be handled carefully due to its thermal and explosive sensitivity.[18][19] The diazotization protocol typically starts by dissolving the aromatic amine (ArNH₂, such as aniline) in concentrated hydrochloric acid (HCl), often as the hydrochloride salt for better solubility, in a volume of water sufficient to maintain a concentration around 1–2 M. The mixture is cooled to 0–5°C using an ice-salt bath to prevent decomposition. An aqueous solution of sodium nitrite (NaNO₂, approximately 1.05–1.1 equivalents) is then added dropwise over 15–30 minutes while maintaining the temperature below 7°C with vigorous stirring; the endpoint is confirmed by a negative test for excess nitrous acid using starch-iodide paper. The reaction mixture is stirred for an additional 30–60 minutes at 0°C to ensure complete formation of the arenediazonium chloride. This low-temperature control is critical to minimize side reactions, as diazonium salts are prone to decomposition at higher temperatures.[18][19][20] For the anion exchange, excess aqueous tetrafluoroboric acid (HBF₄, 48% w/w, 1.1–1.5 equivalents) is added slowly to the cold diazonium chloride solution (maintained below 0–5°C) with continued stirring. The less soluble arenediazonium tetrafluoroborate precipitates as a white to light-colored solid. The mixture is cooled further (e.g., to –5°C or using an ice bath) for 20–30 minutes to maximize precipitation yield. The solid is then collected by vacuum filtration on a Büchner funnel, typically yielding 70–90% after isolation. The precipitate is washed sequentially with ice-cold water (to remove chloride ions), cold methanol or ethanol (to remove impurities), and cold diethyl ether (to dry and remove residual solvents), ensuring all washes are chilled to avoid decomposition.[18][19][21] Drying of the arenediazonium tetrafluoroborate is performed under vacuum at room temperature in a desiccator or near a fume hood to prevent moisture absorption and premature decomposition, which can occur above 20–25°C or upon exposure to light. The dry salt is obtained as a fluffy, crystalline solid and should be stored in the dark at low temperature (e.g., 0–5°C) for stability. Yields for this intermediate are generally high (80–95% for simple aryl systems like benzenediazonium tetrafluoroborate), but purification by recrystallization from acetone-ether may be necessary for sensitive substrates.[18][19] Safety precautions are paramount during preparation, as the diazotization step generates hazardous nitrogen dioxide (NO₂) fumes, necessitating conduction in a well-ventilated fume hood. Tetrafluoroboric acid is corrosive and can cause severe burns; protective gloves, goggles, and clothing are required. Due to the explosive potential of dry diazonium salts upon heating or shock, reactions are limited to laboratory scales (typically <100 g of amine) to minimize risks, and waste should be quenched with base before disposal.[18][4][19]Decomposition and Isolation
The thermal decomposition of the dry aryldiazonium tetrafluoroborate salt is carried out by heating the solid in a flask, often on a sand bath or with direct flame, starting gently until decomposition initiates, then more vigorously at 100–150 °C under an inert atmosphere until evolution of nitrogen gas ceases, which typically requires 30 minutes to 2 hours depending on the substrate.[18][4] This step generates the aryl fluoride along with gaseous nitrogen and boron trifluoride as byproducts. To optimize yields and minimize side reactions such as oxidation, conducting the decomposition under an inert atmosphere like nitrogen is recommended, with typical yields ranging from 50–90% for various aryl fluorides.[4] Following decomposition, the crude aryl fluoride is isolated either by sublimation under reduced pressure, which allows the volatile product to collect away from the residue, or by extraction into an organic solvent such as diethyl ether.[22] The extract is then dried and purified by distillation under reduced pressure to afford the pure aryl fluoride.[22] The gaseous byproduct is handled by passing it through a lime (CaCO/CaO) trap or an aqueous base solution to neutralize and absorb it safely, preventing corrosion and environmental release.[23]Variations and Improvements
Alternative Anions
In the Balz–Schiemann reaction, alternative anions such as hexafluorophosphate (PF₆⁻) and hexafluoroantimonate (SbF₆⁻) serve as substitutes for the conventional tetrafluoroborate (BF₄⁻) counterion, offering improvements in yield and handling properties for certain substrates. These variations maintain the core decomposition pathway but leverage the distinct chemical behaviors of the anions to mitigate limitations like lower efficiency with electron-rich arenes in the standard method.[7] The hexafluorophosphate variant involves thermal decomposition of aryldiazonium hexafluorophosphates ([ArN₂]PF₆) to yield the corresponding aryl fluoride (ArF), phosphorus pentafluoride (PF₅), and nitrogen gas (N₂). This approach achieves modest yield improvements for some substrates, attributed to enhanced stability and reduced side reactions. The method was developed in the 1960s.[7] Hexafluoroantimonate salts ([ArN₂]SbF₆) undergo analogous decomposition to ArF, N₂, and antimony pentafluoride (SbF₅), providing yield enhancements for select substrates but at the cost of greater toxicity owing to the antimony component. These anions generally offer superior solubility in organic solvents and improved thermal stability relative to BF₄⁻, facilitating easier isolation and decomposition control.[7][4] The following table compares yields for representative substrates using BF₄⁻ versus PF₆⁻, illustrating the typical gains with the alternative anion (data for SbF₆⁻ follows similar trends but varies by substrate):| Substrate | BF₄⁻ yield (%) | PF₆⁻ yield (%) |
|---|---|---|
| p-Toluidine | 70 | 71 |
| p-Nitroaniline | 40–58 | 63 |
| p-Aminobenzoic acid | 40 | 49 |