Barton reaction

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.{{Cite journal | doi = 10.15227/orgsyn.016.0007| title = N-Butyl Nitrite| journal = Organic Syntheses| volume = 16| pages = 7| year = 1936}} 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.{{Cite journal | doi = 10.1021/cr60151a001| title = Nitrosyl Chloride| journal = Chemical Reviews| volume = 48| issue = 3| pages = 319–396| year = 1951| last1 = Beckham | first1 = L. J. | last2 = Fessler | first2 = W. A. | last3 = Kise | first3 = M. A. | pmid = 24541207}} The reaction of nitrosyl chloride with aromatic alcohols generally yields nitroso compounds and other over-oxidation products.

The Barton reaction commences with a photochemically induced cleavage of the nitrite O-N bond, typically using a high pressure mercury lamp.{{Cite journal | doi = 10.1016/j.tet.2008.12.063| title = Microflow photo-radical reaction using a compact light source: Application to the Barton reaction leading to a key intermediate for myriceric acid A| journal = Tetrahedron| volume = 65| issue = 8| pages = 1593–1598| year = 2009| last1 = Sugimoto | first1 = A. | last2 = Fukuyama | first2 = T. | last3 = Sumino | first3 = Y. | last4 = Takagi | first4 = M. | last5 = Ryu | first5 = I. }} 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.

File:Barton_reaction_mechanism.svg

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. The second example results in a chain elongation product with the oxime formed 2 carbon units further from the oxygen than normal.{{Cite journal|last1=Petrovic|first1=G.|last2=Cekovic|first2=Z.|date=1997|title=Free radical alkylation of the remote nonactivated δ-carbon atom|journal=Tetrahedron Lett.|volume=38|issue=4|pages=627–630|doi=10.1016/s0040-4039(96)02357-x}}

This mechanistic hypothesis is supported by kinetic isotope effect experiments.{{Cite journal | doi = 10.1039/P19790001159| title = The mechanism of the barton reaction| journal = Journal of the Chemical Society, Perkin Transactions 1| pages = 1159| year = 1979| last1 = Barton | first1 = D. H. R. | last2 = Hesse | first2 = R. H. | last3 = Pechet | first3 = M. M. | last4 = Smith | first4 = L. C. | hdl = 1893/35137 | hdl-access = free}} 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.{{Cite journal | doi = 10.1021/ja01056a035| title = The Mechanism of the Barton Reaction| journal = Journal of the American Chemical Society| volume = 86| issue = 2| pages = 265–268| year = 1964| last1 = Akhtar | first1 = M.| last2 = Pechet | first2 = M. M.}} 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.{{Cite journal | doi = 10.1016/S0040-4039(00)80319-6| title = Intramolecular cyclization of alkenyl radicals generated by 1,5-hydrogen transfer to alkoxy radicals| journal = Tetrahedron Letters| volume = 29| issue = 12| pages = 1441–1444| year = 1988| last1 = Čeković | first1 = Ẑ. | last2 = Ilijev | first2 = D.}}

In rare cases, it appears that the alkoxyl radical may epimerize before hydrogen atom abstraction.{{Cite journal | doi = 10.1021/jo01067a671| title = Communications- Epimerization in a Nitrite Ester Photolysis| journal = The Journal of Organic Chemistry| volume = 26| issue = 9| pages = 3617–3618| year = 1961| last1 = Nickson | first1 = A. | last2 = Mahajan | first2 = J. | last3 = McGuire | first3 = F. }}

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.{{Cite journal | doi = 10.1016/S0040-4020(03)01202-X| title = Reactions of δ-carbon radicals generated by 1,5-hydrogen transfer to alkoxyl radicals| journal = Tetrahedron| volume = 59| issue = 41| pages = 8073–8090| year = 2003| last1 = Čeković | first1 = Ž. }} 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.{{Cite journal | doi = 10.1021/ja00177a009| title = Transition structures for hydrogen atom transfers to oxygen. Comparisons of intermolecular and intramolecular processes, and open- and closed-shell systems| journal = Journal of the American Chemical Society| volume = 112| issue = 21| pages = 7508–7514| year = 1990| last1 = Dorigo | first1 = A. E. | last2 = McCarrick | first2 = M. A. | last3 = Loncharich | first3 = R. J. | last4 = Houk | first4 = K. N.}} 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.{{Cite journal | doi = 10.1007/s10600-006-0003-z| title = Ozonolysis of Ricinolic Acid Derivatives and Transformations of the Ozonolysis Products under Barton Reaction Conditions| journal = Chemistry of Natural Compounds| volume = 41| issue = 6| pages = 643–649| year = 2005| last1 = Ishmuratov | first1 = G. Y. | last2 = Kharisov | first2 = R. Y. | last3 = Shayakhmetova | first3 = A. K. | last4 = Botsman | first4 = L. P.| last5 = Shitikova | first5 = O. V.| last6 = Tolstikov | first6 = G. A.| s2cid = 43171151}}

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.{{Cite journal | doi = 10.1021/ja00948a036| title = Some Radical Exchange Reactions during Nitrite Ester Photolysis1| journal = Journal of the American Chemical Society| volume = 87| issue = 20| pages = 4601–4607| year = 1965| last1 = Akhtar | first1 = M.| last2 = Barton | first2 = D. H. R.| last3 = Sammes | first3 = P. G.}} 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.{{Cite journal | doi = 10.1016/S0040-4039(00)99651-5| title = Fragmentation of isopulegol by a radical process| journal = Tetrahedron Letters| volume = 30| issue = 17| pages = 2213–2216| year = 1989| last1 = Bulliard | first1 = M. | last2 = Balme | first2 = G. V. | last3 = Gore | first3 = J. }}

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.{{Cite journal | doi = 10.1039/b000705f| title = Radical translocation reactions in synthesis| journal = Chemical Society Reviews| volume = 30| issue = 2| pages = 94–103| year = 2001| last1 = Robertson | first1 = J. | last2 = Pillai | first2 = J. | last3 = Lush | first3 = R. K. }} 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.

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.{{Cite journal | doi = 10.1021/ja01070a039| title = Radical Exchange during Nitrite Photolysis| journal = Journal of the American Chemical Society| volume = 86| issue = 16| pages = 3394–3395| year = 1964| last1 = Akhtar | first1 = M.| last2 = Barton | first2 = D. H. R.| last3 = Sammes | first3 = P. G.}}

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.{{Cite journal | doi = 10.1016/S0040-4020(98)01110-7| title = 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| journal = Tetrahedron| volume = 55| issue = 5| pages = 1377–1390| year = 1999| last1 = Petrović | first1 = G. | last2 = Čeković | first2 = Ž. }}

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.{{Cite journal | doi = 10.1039/P19730002402| title = Nitrite photolysis in the presence of oxygen. An improved synthesis of 32-oxygenated lanostanes| journal = Journal of the Chemical Society, Perkin Transactions 1| pages = 2402| year = 1973| last1 = Allen | first1 = J. | last2 = Boar | first2 = R. B. | last3 = McGhie | first3 = J. F. | last4 = Barton | first4 = D. H. R. }}

In a publication immediately proceeding Barton's initial disclosure of the methodology in the Journal of the American Chemical Society, a synthesis of aldosterone acetate is demonstrated.{{Cite journal | doi = 10.1021/ja01495a062| title = A Synthesis of Aldosterone Acetate| journal = Journal of the American Chemical Society| volume = 82| issue = 10| pages = 2641| year = 1960| last1 = Barton | first1 = D. H. R.| last2 = Beaton | first2 = J. M.}} Allowing corticosterone acetate to react with nitrosyl chloride in dry pyridine yields the nitrite. Subsequently, irradiation under inert atmosphere followed by treatment with aqueous sodium nitrite selectively gives the desired oxime. The oxime is then acetylated and hydrolyzed to yield the natural product hemiacetal.

File:Aldosterone_Acetate_Barton_Reaction.png

After a short synthesis to obtain the desired spiro-[5.4] system, Nobel laureaute E.J. Corey and co-workers employed a Barton reaction to selectively introduce an oxime in a 1,3-diaxial position to the nitrite ester. The oxime is converted to a lactam via a Beckmann rearrangement and then reduced to the natural product.{{cite journal | doi = 10.1021/ja00835a039 | volume=97 | title=Simple total synthesis of (+-)-perhydrohistrionicotoxin | journal=Journal of the American Chemical Society | pages=430–431 | year=1975 | last1 = Corey | first1 = E. J.| issue=2 | pmid=1169269 }}

File:Corey Barton Reaction Perhydrohistrionicotoxin.png

Corey again employed the Barton reaction in the synthesis of Azadiradione, a member of the limonoid family of natural products. In this case, nitrosylsulfuric acid is used in place of nitrosyl chloride.{{Cite journal | doi = 10.1016/S0040-4039(00)99392-4| title = Synthesis of a limonoid, azadiradione| journal = Tetrahedron Letters| volume = 30| issue = 23| pages = 3023–3026| year = 1989| last1 = Corey | first1 = E. J. | last2 = Hahl | first2 = R. W. }}

File:Azadiradione Corey Barton Reaction.png

In the process of preparing a series of derivatives of the triterpenoid allobetulin, Dehan and coworkers observed a remarkable transformation resulting from two consecutive 1,5-hydrogen atom transfers. While the product of the single 1,5-hydrogen atom transfer was also observed, the former transformation represent a formal 1,7-hydrogen atom transfer across an enormous distance.{{Cite journal | doi = 10.3390/molecules16032443| title = Allobetulin and Its Derivatives: Synthesis and Biological Activity| journal = Molecules| volume = 16| issue = 12| pages = 2443–2466| year = 2011| last1 = Dehaen | first1 = W. | last2 = Mashentseva | first2 = A. A. | last3 = Seitembetov | first3 = T. S. | pmc = 6259842 | pmid=21403601| doi-access = free}}

File:Dehan Allobetullin Barton Reaction.png

{{reflist}}

• 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}}.

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Category:Free radical reactions

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