Directed ortho metalation (DoM) is an adaptation of

electrophilic aromatic substitution Electrophilic aromatic substitution is an organic reaction in which an atom that is attached to an aromatic system (usually hydrogen) is replaced by an electrophile. Some of the most important electrophilic aromatic substitutions are aromatic ni ...

in which

electrophile In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carries ...

s attach themselves exclusively to the

ortho- Ortho- is a Greek prefix meaning “straight”, “upright”, “right” or “correct”. Ortho may refer to: * Ortho, Belgium, a village in the Belgian province of Luxembourg In science * arene substitution patterns, two substituents that ...

position of a direct metalation group or DMG through the intermediary of an aryllithium compound. The DMG interacts with lithium through a

hetero atom In chemistry, a heteroatom () is, strictly, any atom that is not carbon or hydrogen. Organic chemistry In practice, the term is usually used more specifically to indicate that non-carbon atoms have replaced carbon in the backbone of the molecul ...

. Examples of DMG's are the

methoxy In organic chemistry, a methoxy group is the functional group consisting of a methyl group bound to oxygen. This alkoxy group has the formula . On a benzene ring, the Hammett equation classifies a methoxy substituent at the ''para'' position a ...

group, a

tertiary amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such a ...

group and an

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...

group.The compound can be produced by directed lithiation of anisole. The general principle is outlined in ''scheme 1''. An aromatic ring system with a DMG group 1 interacts with an

alkyllithium In organometallic chemistry, organolithium reagents are chemical compounds that contain carbon–lithium (C–Li) bonds. These reagents are important in organic synthesis, and are frequently used to transfer the organic group or the lithium atom ...

such as ''n''-butyllithium in its specific aggregation state (hence (R-Li)_n) to intermediate 2 since the hetero atom on the DMG is a

Lewis base A Lewis acid (named for the American physical chemist Gilbert N. Lewis) is a chemical species that contains an empty orbital which is capable of accepting an electron pair from a Lewis base to form a Lewis adduct. A Lewis base, then, is any sp ...

and lithium the

Lewis acid A Lewis acid (named for the American physical chemist Gilbert N. Lewis) is a chemical species that contains an empty orbital which is capable of accepting an electron pair from a Lewis base to form a Lewis adduct. A Lewis base, then, is any sp ...

. The very basic alkyllithium then deprotonates the ring in the nearest ortho- position forming the aryllithium 3 all the while maintaining the acid-base interaction. An electrophile reacts in the next phase in an

with a strong preference for the lithium ipso position replacing the lithium atom. Ordinary electrophilic substitutions with an

activating group In electrophilic aromatic substitution reactions, existing substituent groups on the aromatic ring influence the overall reaction rate or have a directing effect on positional isomer of the products that are formed. An electron donating group (ED ...

show preference for both the ortho and para position, this reaction demonstrates increased

regioselectivity In chemistry, regioselectivity is the preference of chemical bonding or breaking in one direction over all other possible directions. It can often apply to which of many possible positions a reagent will affect, such as which proton a strong base ...

because the ortho position alone is targeted. This reaction type was reported independently by

Henry Gilman Henry Gilman (May 9, 1893 – November 7, 1986) was an American organic chemist known as the father of organometallic chemistry, the field within which his most notable work was done. He discovered the Gilman reagent, which bears his name. Earl ...

and

Georg Wittig Georg Wittig (; 16 June 1897 – 26 August 1987) was a German chemist who reported a method for synthesis of alkenes from aldehydes and ketones using compounds called phosphonium ylides in the Wittig reaction. He shared the Nobel Prize in Che ...

around 1940.

Examples

DOM has traditionally been applied to tertiary anilines and benzyl amines. The method has also been applied to the synthesis of

enantiopure In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical anti ...

benzyl amines in ''scheme 3'', which involves ortho-lithiation of ''tert''-butyl phenyl sulfoxide. On approach to the lithium intermediate, the bulky

tosyl In organic chemistry, a toluenesulfonyl group (tosyl group, abbreviated Ts or Tos) is a univalent functional group with the chemical formula –. It consists of a Toluene, tolyl group, –, joined to a sulfonyl group, ––, with the open vale ...

group on the

imine In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bo ...

is responsible for the asymmetric induction taking place. In another application DOM is applied in placing a bulky

tert-butyl In organic chemistry, butyl is a four-carbon alkyl radical or substituent group with general chemical formula , derived from either of the two isomers (''n''-butane and isobutane) of butane. The isomer ''n''-butane can connect in two ways, givi ...

group in an ortho position (''scheme 4''). The lithiation is a

nucleophilic aromatic substitution A nucleophilic aromatic substitution is a substitution reaction in organic chemistry in which the nucleophile displaces a good leaving group, such as a halide, on an aromatic ring. Aromatic rings are usually nucleophilic, but some aromatic compou ...

and the subsequent reaction to the

sulfoxide In organic chemistry, a sulfoxide, also called a sulphoxide, is an organosulfur compound containing a sulfinyl () functional group attached to two carbon atoms. It is a polar functional group. Sulfoxides are oxidized derivatives of sulfides. E ...

. In the final step ''tert''-butyllithium acts as a

nucleophile In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...

in another nucleophilic aromatic substitution through an anionic intermediate. D''o''M has also been applied combined with a

Suzuki reaction The Suzuki reaction is an organic reaction, classified as a cross-coupling reaction, where the coupling partners are a boronic acid and an organohalide and the catalyst is a palladium(0) complex. It was first published in 1979 by Akira Suzuki, ...

in a

one-pot synthesis In chemistry a one-pot synthesis is a strategy to improve the efficiency of a chemical reaction whereby a reactant is subjected to successive chemical reactions in just one reactor. This is much desired by chemists because avoiding a lengthy sepa ...

Thiophenol derivatives

DOM has also been used with

thiophenol Thiophenol is an organosulfur compound with the formula C6H5SH, sometimes abbreviated as PhSH. This foul-smelling colorless liquid is the simplest aromatic thiol. The chemical structures of thiophenol and its derivatives are analogous to phenols ...

s to prepare compounds that are useful as hindered ligands.

Related reaction

Directed metallation is not limited to lithium intermediates or even to an ortho preference. In one study it is found that the reaction product of N,N-dimethylaniline with a complex of TMEDA, sodium salt of

TMP TMP can refer to any of the following: Chemistry * 2,2,6,6-Tetramethylpiperidine, an organic chemistry reagent * Thymidine monophosphate, a nucleotide * Trimethoprim, an antibiotic * Trimethyl phosphate, a solvent * Trimethylolpropane, a precurso ...

and di-tert-butylzinc is a

meta Meta (from the Greek μετά, '' meta'', meaning "after" or "beyond") is a prefix meaning "more comprehensive" or "transcending". In modern nomenclature, ''meta''- can also serve as a prefix meaning self-referential, as a field of study or ende ...

zincated complex as a stable crystalline compound. This complex reacts with electrophilic

iodine Iodine is a chemical element with the symbol I and atomic number 53. The heaviest of the stable halogens, it exists as a semi-lustrous, non-metallic solid at standard conditions that melts to form a deep violet liquid at , and boils to a vi ...

to N,N-dimethyl-3-iodoaniline:Solvent

hexane Hexane () is an organic compound, a straight-chain alkane with six carbon atoms and has the molecular formula C6H14. It is a colorless liquid, odorless when pure, and with boiling points approximately . It is widely used as a cheap, relatively ...

reaction at

room temperature Colloquially, "room temperature" is a range of air temperatures that most people prefer for indoor settings. It feels comfortable to a person when they are wearing typical indoor clothing. Human comfort can extend beyond this range depending on ...

. Selected bond lengths in 2: Zn-C bond 203.5 pm in plane with aryl plane, Na-C bond 269 pm at 76° to aryl plane

References

{{reflist Substitution reactions