巴頓反應
巴頓反應（Barton反應）以英國化學家德里克·巴頓命名，也稱為巴頓亞硝酸酯反應[1]反應中亞硝酸酯光解生成δ-亞硝基醇。反應經由RO–NO鍵均裂，氧自由基奪氫，而後自由基結合的機理。[2]
類似的反應是以鹵代胺為原料的Hofmann-Löffler-Freytag反應。
該反應是在1960年發現的，其發現者是諾貝爾獎獲得者德里克·巴頓爵士。[3] 巴頓1969年的諾貝爾化學獎是因為他在理解有機分子構象方面的工作而獲獎，這項工作對於實現巴頓反應的實用性至關重要。[4]
Barton反應涉及RO-NO均勻斷裂，然後進行δ-奪氫反應，自由基重組和互變異構反應形成肟。[5]δ-氫的選擇性是6-元基團中間體的構象的結果。 通常，可以容易地預測氫原子奪取的位置。 這允許區域選擇性和立體選擇性地將功能性引入到具有高產率的複雜分子中。 由於其獨特的衍生其他惰性底物的能力，巴頓在20世紀60年代廣泛使用這種反應來製造許多非天然的類固醇類似物。 [6]
雖然Barton反應尚未得到許多其他有機反應的普及或廣泛使用，同樣的是機理上類似的Hofmann-Löffler-Freytag反應，但它代表了碳氫鍵活化化學的第一個例子，在工業和學術化學界這個領域現在是許多前沿研究的主題。[7]
亞硝酸烷基酯的製備
The unusual alkyl nitrite starting material of the Barton reaction is prepared by attack of an alcohol on a nitrosylium cation generated in situ by dehydration of doubly protonated nitrous acid.[8] This series of steps is mechanistically identical to the first half of the mechanism formation of the more well-known aryl and alkyl diazonium salts.
While the synthesis of alkyl nitrites from nitrosyl chloride is known and oft-employed in the context of complex molecule synthesis, the reaction is reversible and the products are in thermodynamic equilibrium with the starting material. Furthermore, nitrosyl chloride is a powerful oxidizing agent, and oxidation of the alcohols with concomitant chlorination has been observed.[9] The reaction of nitrosyl chloride with aromatic alcohols generally yields nitroso compounds and other over-oxidation products.
反應機理和區域選擇性
The Barton reaction commences with a photochemically induced cleavage of the nitrite O-N bond, typically using a high pressure mercury lamp.[10] This produces an alkyoxyl radical which immediately abstracts a hydrogen atom from the δ-carbon. In the absence of other radical sources or other proximal reactive groups, the alkyl radical recombines with the nitrosyl radical. The resultant nitroso compounds undergoes tautomerization to the isolated oxime product.
The carbon centered radical can be intercepted by other radical sources such as iodine or acrylonitrile. The first instance results in the δ-hydrogen being replaced with iodine, then subsequent cyclization to a tetrahydrofuran by an SN2 reaction.[11] The second example results in a chain elongation product with the oxime formed 2 carbon units further from the oxygen than normal.[12]
This mechanistic hypothesis is supported by kinetic isotope effect experiments.[13] Isotopic labeling of the nitrite with 15N has shown the mechanism non-『caged』 and that the nitrosyl radical formed from a given nitrite recombines randomly with other alkyl radicals. However, recombination of the nitrosyl radical with the alkoxyl radical (a reversal of the homolytic cleavage) has been shown to proceed without scrambling of isotope labels.[14] This lack of tight radical pairing is also supported by the observation that alkyl radicals generated by Barton conditions can undergo radical cyclization while analogous intermediates generated by lead tetraacetate oxidation do not.[15]
In rare cases, it appears that the alkoxyl radical may epimerize before hydrogen atom abstraction.[16]
Most commonly, including steroidal systems, the hydrogen atom is abstracted from a methyl group that has a 1,3 diaxial relationship with the alkoxyl radical.[17] In the absence of a hydrogen on the δ-carbon, or when the particular conformation of the substrate orients the ε-carbon close together, 1,6-hydrogen atom transfer is the favored process. However, these reactions tend to be an order of magnitude slower than the corresponding 1,5-hydrogen atom transfer.
Computational studies have shown that this preference for 1,5-hydrogen atom transfer over 1,6-hydrogen atom transfer appears to be entropically favored rather than a result of a particular stable 『chair-like’ transition state.[18] In fact, it has been calculated that the 1,6-hydrogen atom transfer proceeds through a transition that is about 0.8 kcal/mol lower than that of the 1,5.
In acyclic systems, δ-hydrogen abstraction is still observed, however, alpha-hydrogen abstraction to form the corresponding ketone competes.[19]
In certain cases, particularly nitrites derived from cyclopentyl alcohols, the oxygen-centered radical prefers to react via C-C bond cleavage as opposed to H-atom abstraction.[11] For example, when subjected to Barton conditions, cyclopentyl nitrite forms glutaraldehyde monoxime. This is also observed in cases where the radical intermediate formed by fragmentation is particularly stable, such as the allylic radical formed by the fragmentation of isopulegol nitrite.[20]
變體
In rigid systems such as aldosterone, the 1,5-hydrogen atom transfer is exceedingly fast, with a rate constant on the order of 10^7 s-1. Similar intermolecular H-atom transfer can be up to 100 times slower.[21] Furthermore, the hydrogen atom transfer benefits from the formation of a stronger O-H bond at the expense of a weaker C-H bond. For the formation of a primary, second, or tertiary alkyl radical from an alkoxyl radical, there is a driving force of 3 kcal/mol, 5 kcal/mol, and 9 kcal/mol, respectively.[17]
The alkyl radical formed after hydrogen atom transfer is susceptible to standard radical reactions when scavengers are present in sufficient excess to outcompete the nitrosyl radical. Soon after their initial disclosure, Barton and co-workers reported the trapping of the radical with I2 and CCl3Br (as Iodine and Bromine radical sources, respectively) to form the δ-halo-alcohol. These halohydrin species can be cyclized to the corresponding tetrahydropyran derivates under basic conditions.[22]
Large excesses of activated alkenes can be used to intercept the alkyl radical and results in formation of a C-C bond from an unactivated C-H bond.[23]
In the presence of oxygen, the alkyl radical is trapped and forms an organic peroxy radical. This intermediate is trapped by the nitrosyl radical and then isomerizes to give a δ-nitrate ester which, while both acid- and base-stable, can be reduced to the corresponding alcohol under mild conditions.[24]
參考文獻
- ^ D. H. R. Barton, J. M. Beaton, L. E. Geller, and M. M. Pechet. A New Photochemical Reaction. Journal of the American Chemical Society. 1961, 83 (19): 4076–4083. doi:10.1021/ja01480a030.
- ^ IUPAC Goldbook (PDF). [2008-06-27]. （原始內容 (PDF)存檔於2007-06-09）.
- ^ Barton, D. H. R.; Beaton, J. M.; Geller, L. E.; Pechet, M. M. A New Photochemical Reaction. Journal of the American Chemical Society. 1960, 82 (10): 2640–2641. doi:10.1021/ja01495a061.
- ^ Barton, D. H. R.; Beaton, J. M.; Geller, L. E.; Pechet, M. M. A New Photochemical Reaction1. Journal of the American Chemical Society. 1961, 83 (19): 4076–4083. doi:10.1021/ja01480a030.
- ^ 國際純化學和應用化學聯合會，化學術語概略，第二版。（金皮書）(1997)。在線校正版: (2006–) "Barton Reaction"。doi:10.1351/goldbook.B00599
- ^ Nussbaum, A. L.; Yuan, E. P.; Robinson, C. H.; Mitchell, A.; Oliveto, E. P.; Beaton, J. M.; Barton, D. H. R. The Photolysis of Organic Nitrites. VII. Fragmentation of the Steroidal Side Chain. The Journal of Organic Chemistry. 1962, 27: 20–23. doi:10.1021/jo01048a004.
- ^ Gutekunst, W. R.; Baran, P. S. C–H functionalization logic in total synthesis. Chemical Society Reviews. 2011, 40 (4): 1976. doi:10.1039/c0cs00182a.
- ^ N-Butyl Nitrite. Organic Syntheses. 1936, 16: 7. doi:10.15227/orgsyn.016.0007.
- ^ Beckham, L. J.; Fessler, W. A.; Kise, M. A. Nitrosyl Chloride. Chemical Reviews. 1951, 48 (3): 319–396. PMID 24541207. doi:10.1021/cr60151a001.
- ^ Sugimoto, A.; Fukuyama, T.; Sumino, Y.; Takagi, M.; Ryu, I. Microflow photo-radical reaction using a compact light source: Application to the Barton reaction leading to a key intermediate for myriceric acid A. Tetrahedron. 2009, 65 (8): 1593–1598. doi:10.1016/j.tet.2008.12.063.
- ^ 11.0 11.1 Akhtar, M.; Barton, D. H. R.; Sammes, P. G. Some Radical Exchange Reactions during Nitrite Ester Photolysis1. Journal of the American Chemical Society. 1965, 87 (20): 4601–4607. doi:10.1021/ja00948a036.
- ^ Petrovic, G.; Cekovic, Z. Free radical alkylation of the remote nonactivated δ-carbon atom. Tetrahedron Lett. 1997, 38 (4): 627–630. doi:10.1016/s0040-4039(96)02357-x.
- ^ Barton, D. H. R.; Hesse, R. H.; Pechet, M. M.; Smith, L. C. The mechanism of the barton reaction. Journal of the Chemical Society, Perkin Transactions 1. 1979: 1159. doi:10.1039/P19790001159.
- ^ Akhtar, M.; Pechet, M. M. The Mechanism of the Barton Reaction. Journal of the American Chemical Society. 1964, 86 (2): 265–268. doi:10.1021/ja01056a035.
- ^ Čeković, Ẑ.; Ilijev, D. Intramolecular cyclization of alkenyl radicals generated by 1,5-hydrogen transfer to alkoxy radicals. Tetrahedron Letters. 1988, 29 (12): 1441–1444. doi:10.1016/S0040-4039(00)80319-6.
- ^ Nickson, A.; Mahajan, J.; McGuire, F. Communications- Epimerization in a Nitrite Ester Photolysis. The Journal of Organic Chemistry. 1961, 26 (9): 3617–3618. doi:10.1021/jo01067a671.
- ^ 17.0 17.1 Čeković, Ž. Reactions of δ-carbon radicals generated by 1,5-hydrogen transfer to alkoxyl radicals. Tetrahedron. 2003, 59 (41): 8073–8090. doi:10.1016/S0040-4020(03)01202-X.
- ^ Dorigo, A. E.; McCarrick, M. A.; Loncharich, R. J.; Houk, K. N. Transition structures for hydrogen atom transfers to oxygen. Comparisons of intermolecular and intramolecular processes, and open- and closed-shell systems. Journal of the American Chemical Society. 1990, 112 (21): 7508–7514. doi:10.1021/ja00177a009.
- ^ Ishmuratov, G. Y.; Kharisov, R. Y.; Shayakhmetova, A. K.; Botsman, L. P.; Shitikova, O. V.; Tolstikov, G. A. Ozonolysis of Ricinolic Acid Derivatives and Transformations of the Ozonolysis Products under Barton Reaction Conditions. Chemistry of Natural Compounds. 2005, 41 (6): 643–649. S2CID 43171151. doi:10.1007/s10600-006-0003-z.
- ^ Bulliard, M.; Balme, G. V.; Gore, J. Fragmentation of isopulegol by a radical process. Tetrahedron Letters. 1989, 30 (17): 2213–2216. doi:10.1016/S0040-4039(00)99651-5.
- ^ Robertson, J.; Pillai, J.; Lush, R. K. Radical translocation reactions in synthesis. Chemical Society Reviews. 2001, 30 (2): 94–103. doi:10.1039/b000705f.
- ^ Akhtar, M.; Barton, D. H. R.; Sammes, P. G. Radical Exchange during Nitrite Photolysis. Journal of the American Chemical Society. 1964, 86 (16): 3394–3395. doi:10.1021/ja01070a039.
- ^ Petrović, G.; Čeković, Ž. Alkylation of remote non-activated δ-carbon atoms: Addition of δ-carbon radicals, generated by 1,5-hydrogen transfer in alkoxy radical intermediates, to activated olefins. Tetrahedron. 1999, 55 (5): 1377–1390. doi:10.1016/S0040-4020(98)01110-7.
- ^ Allen, J.; Boar, R. B.; McGhie, J. F.; Barton, D. H. R. Nitrite photolysis in the presence of oxygen. An improved synthesis of 32-oxygenated lanostanes. Journal of the Chemical Society, Perkin Transactions 1. 1973: 2402. doi:10.1039/P19730002402.
- László Kürti, Barbara Czakó: Strategic Applications of Named Reactions in Organic Synthesis; Elsevier Academic Press, Burlington-San Diego-London 2005, 1. Edition; ISBN 0-12-369483-3.