Barton Reaction
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The Barton reaction, also known as the Barton nitrite ester reaction, is a photochemical reaction that involves the
photolysis Photodissociation, photolysis, photodecomposition, or photofragmentation is a chemical reaction in which molecules of a chemical compound are broken down by absorption of light or photons. It is defined as the interaction of one or more photons wi ...
of an alkyl
nitrite The nitrite polyatomic ion, ion has the chemical formula . Nitrite (mostly sodium nitrite) is widely used throughout chemical and pharmaceutical industries. The nitrite anion is a pervasive intermediate in the nitrogen cycle in nature. The name ...
to form a δ-
nitroso In organic chemistry, nitroso refers to a functional group in which the nitric oxide () group is attached to an organic moiety. As such, various nitroso groups can be categorized as ''C''-nitroso compounds (e.g., nitrosoalkanes; ), ''S''-nitros ...
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
. Discovered in 1960, the reaction is named for its discoverer, Nobel laureate Sir
Derek Barton Sir Derek Harold Richard Barton (8 September 1918 – 16 March 1998) was an English organic chemist and Nobel Prize laureate for 1969. Education and early life Barton was born in Gravesend, Kent, to William Thomas and Maude Henrietta Barton ...
. Barton's
Nobel Prize in Chemistry The Nobel Prize in Chemistry () is awarded annually by the Royal Swedish Academy of Sciences to scientists in the various fields of chemistry. It is one of the five Nobel Prizes established by the will of Alfred Nobel in 1895, awarded for outst ...
in 1969 was awarded for his work on understanding conformations of organic molecules, work which was key to realizing the utility of the Barton Reaction. The Barton reaction involves a homolytic RO–NO cleavage, followed by δ- hydrogen abstraction,
free radical A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing. Ageing Biogerontology Biological processes Causes of death Cellular processes Gerontology Life extension Metabolic disorders Metabolism ...
recombination, and tautomerization to form an
oxime In organic chemistry, an oxime is an organic compound belonging to the imines, with the general Chemical formula, formula , where R is an organic Side chain, side-chain and R' may be hydrogen, forming an aldoxime, or another organic functional g ...
. Selectivity for the δ-hydrogen is a result of the conformation of the 6-membered radical intermediate. Often, the site of hydrogen atom abstraction can be easily predicted. This allows the regio- and stereo-selective introduction of functionality into complicated molecules with high yield. Due to its unique property at the time to change otherwise inert substrates, Barton used this reaction extensively in the 1960s to create a number of unnatural steroid analogues. While the Barton reaction has not enjoyed the popularity or widespread use of many other organic reactions, together with the mechanistically similar
Hofmann–Löffler reaction In organic chemistry, the Hofmann–Löffler reaction (also referred to as Hofmann–Löffler–Freytag reaction, Löffler–Freytag reaction, Löffler–Hofmann reaction, as well as Löffler's method) is a cyclization reaction with remote C–H ...
it represents one of the first examples of C-H activation chemistry, a field which is now the topic of much frontline research in industrial and academic chemistry circles.


Preparation of alkyl nitrites

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. 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 Nitrosyl chloride is the chemical compound with the formula NOCl. It is a yellow gas that is commonly encountered as a component of aqua regia, a mixture of 3 parts concentrated hydrochloric acid and 1 part of concentrated nitric acid. It is a str ...
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. The reaction of nitrosyl chloride with aromatic alcohols generally yields nitroso compounds and other over-oxidation products.


Reaction mechanism and regioselectivity

The Barton reaction commences with a photochemically induced cleavage of the nitrite O-N bond, typically using a high pressure mercury lamp. 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 In chemistry, tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert. The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the reloca ...
to the isolated oxime product. The carbon centered radical can be intercepted by other radical sources such as iodine or
acrylonitrile Acrylonitrile is an organic compound with the formula and the structure . It is a colorless, volatile liquid. It has a pungent odor of garlic or onions. Its molecular structure consists of a vinyl group () linked to a nitrile (). It is an im ...
. The first instance results in the δ-hydrogen being replaced with iodine, then subsequent
cyclization A cyclic compound (or ring compound) is a term for a compound in the field of chemistry in which one or more series of atoms in the compound is connected to form a ring. Rings may vary in size from three to many atoms, and include examples where ...
to a
tetrahydrofuran Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water- miscible organic liquid with low viscosity. It is ...
by an
SN2 reaction The bimolecular nucleophilic substitution (SN2) is a type of reaction mechanism that is common in organic chemistry. In the SN2 reaction, a strong nucleophile forms a new bond to an sp3-hybridised carbon atom via a backside attack, all while t ...
. The second example results in a chain elongation product with the oxime formed 2 carbon units further from the oxygen than normal. This mechanistic hypothesis is supported by
kinetic isotope effect In physical organic chemistry, a kinetic isotope effect (KIE) is the change in the reaction rate of a chemical reaction when one of the atoms in the reactants is replaced by one of its isotopes. Formally, it is the ratio of rate constants for t ...
experiments. 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. 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 Lead(IV) acetate or lead tetraacetate is an metalorganic compound with chemical formula , often abbreviated as , where Ac is acyl. It is a colorless solid that is soluble in nonpolar, organic solvents, indicating that it is not a salt. It is de ...
oxidation do not. In rare cases, it appears that the alkoxyl radical may epimerize before hydrogen atom abstraction. 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. 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 In chemistry, the transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest potential energy along this reaction coordinate. It is often marked w ...
. 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. 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. 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.


Variants

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. 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 Tetrahydropyran (THP) is the organic compound consisting of a saturated six-membered ring containing five carbon atoms and one oxygen atom. It is named by reference to pyran, which contains two double bonds, and may be produced from it by addin ...
derivates under basic conditions. 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. In the presence of
oxygen Oxygen is a chemical element; it has chemical symbol, symbol O and atomic number 8. It is a member of the chalcogen group (periodic table), group in the periodic table, a highly reactivity (chemistry), reactive nonmetal (chemistry), non ...
, 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.


Applications in complex molecule synthesis


Aldosterone acetate

In a publication immediately proceeding Barton's initial disclosure of the methodology in the
Journal of the American Chemical Society The ''Journal of the American Chemical Society'' (also known as JACS) is a weekly peer-reviewed scientific journal that was established in 1879 by the American Chemical Society. The journal has absorbed two other publications in its history, the ...
, a synthesis of
aldosterone Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays ...
acetate is demonstrated. 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 In organic chemistry, a hemiacetal is a functional group the general formula , where is a hydrogen atom or an organic substituent. They generally result from the nucleophilic Addition reaction, addition of an Alcohol (chemistry), alcohol (a compo ...
.


Perhydrohistrionicotoxin

After a short synthesis to obtain the desired spiro- .4system, Nobel laureaute
E.J. Corey Elias James Corey (born July 12, 1928) is an American organic chemist. In 1990, he won the Nobel Prize in Chemistry "for his development of the theory and methodology of organic synthesis", specifically retrosynthetic analysis. Regarded by ma ...
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 A lactam is a Cyclic compound, cyclic amide, formally derived from an amino alkanoic acid through cyclization reactions. The term is a portmanteau of the words ''lactone'' + ''amide''. Nomenclature Greek_alphabet#Letters, Greek prefixes in alpha ...
via a
Beckmann rearrangement The Beckmann rearrangement, named after the German chemist Ernst Otto Beckmann (1853–1923), is a rearrangement reaction, rearrangement of an oxime functional group to substituted amides. The rearrangement has also been successfully performed on ...
and then reduced to the natural product.


Azadiradione

Corey again employed the Barton reaction in the synthesis of
Azadiradione Azadiradione is a naturally occurring compound found in several plants, most notably the neem tree (''Azadirachta indica''). It is a tetracyclic triterpenoid. Sources Azadiradione is the principal active ingredient in neem oil, which is extracte ...
, a member of the limonoid family of natural products. In this case,
nitrosylsulfuric acid Nitrosylsulfuric acid is the chemical compound with the formula . It is a colourless solid that is used industrially in the production of caprolactam, and was formerly part of the lead chamber process for producing sulfuric acid. The compound is t ...
is used in place of nitrosyl chloride.


Allobetulin derivatives

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.


References

* László Kürti, Barbara Czakó: ''Strategic Applications of Named Reactions in Organic Synthesis''; Elsevier Academic Press, Burlington-San Diego-London 2005, 1. Edition; . {{Authority control Free radical reactions Name reactions