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 ca ...

s attach themselves exclusively to the ortho- position of a direct metalation group or DMG through the intermediary of an aryllithium compound. The DMG interacts with lithium through a hetero atom. Examples of DMG's are the methoxy group, a tertiary amine 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 Director may refer to: Literature * ''Director'' (magazine), a British magazine * ''The Director'' (novel), a 1971 novel by Henry Denker * ''The Director'' (play), a 2000 play by Nancy Hasty Music * Director (band), an Irish rock band * ''Di ...

of anisole. The general principle is outlined in ''scheme 1''. An aromatic ring system with a DMG group 1 interacts with an alkyllithium 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 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 Deprotonation (or dehydronation) is the removal (transfer) of a proton (or hydron, or hydrogen cation), (H+) from a Brønsted–Lowry acid in an acid–base reaction.Henry Jakubowski, Biochemistry Online Chapter 2A3, https://employees.csbsju.edu ...

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 ( ...

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 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 ...

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

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, giv ...

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 compoun ...

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 a ...

in another nucleophilic aromatic substitution through an anionic intermediate. D''o''M has also been applied combined with a Suzuki reaction in a one-pot synthesis:

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 phenol ...

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 Tetramethylethylenediamine (TMEDA or TEMED) is a chemical compound with the formula (CH3)2NCH2CH2N(CH3)2. This species is derived from ethylenediamine by replacement of the four amine hydrogens with four methyl groups. It is a colorless liquid, ...

, sodium salt of TMP and di-tert-butylzinc is a meta zincated complex as a stable crystalline compound. This complex reacts with electrophilic

iodine Iodine is a chemical element with the Symbol (chemistry), 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 , ...

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