Directed ortho metalation (DoM) is an adaptation of

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

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 Electric charge, charged, have an ...

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 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 group and an

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a chemical compound, compound with the general formula , where R, R', and R″ represent any group, typically organyl functional group, groups or hydrogen at ...

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 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 ...

. 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 show preference for both the ortho and para position, this reaction demonstrates increased regioselectivity because the ortho position alone is targeted. This reaction type was reported independently by Henry Gilman and Georg Wittig 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 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 bon ...

is responsible for the asymmetric induction taking place. In another application DOM is applied in placing a bulky tert-butyl group in an ortho position (''scheme 4''). The lithiation is a nucleophilic aromatic substitution and the subsequent reaction to the sulfoxide an

. 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 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 phen ...

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

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

hexane Hexane () or ''n''-hexane is an organic compound, a straight-chain alkane with six carbon atoms and the molecular formula C6H14. Hexane is a colorless liquid, odorless when pure, and with a boiling point of approximately . It is widely used as ...

reaction at room temperature. 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