Avant-garde metalating agents: Structural basis of alkali-metal-mediated metalation

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Abstract

Metalation, one of the most useful and widely used synthetic methodologies, transforms a relatively inert carbon-hydrogen bond to a more labile carbon-metal bond. Until recently, most organometallic reagents that facilitate this process have combined strongly electropositive metals, such as lithium, with organic reagents to form highly polar and, by implication, highly reactive carbon-metal bonds. For example, the alkyllithium reagents and bulky lithium amides that are commonly employed for this purpose can suffer from low functional group tolerance. Lithio-products of these reactions generally have low kinetic stabilities. More recently, several groups around the world have pioneered alternative metalation reagents, complex metalators, which can be interpreted as composite molecules or mixtures made up of two or more distinct compound types. Several examples include magnesiate complexes, Lochmann-Schlosser superbases, Kondo and Uchiyama's 2,2,6,6-tetramethylpiperidide (TMP)-zincate complexes, and Knochel's turbo-Grignard and related salt-supported reagents. This Account describes our rational development of novel complex metalators based on existing structural templates and designed to execute alkali-metal-mediated metalations (AMMMs). By changing the nonalkali metal in these structures, we have produced tailor-made dianionic-dicationic structures such as [(TMEDA) center dot Na(mu-TMP)(mu-Bu-n)Mg(TMP)], [(TMEDA) center dot Na(mu-TMP)(mu-Bu-t)Zn(Bu-t)], and [(TMEDA) center dot Li(mu-TMP)Mn(CH2SiMe3)(2)] (TMEDA = N,N,N',N'-tetramethylethylenediamine). These compounds can perform unprecedented magnesiations, zincations, or manganations on aromatic substrates that are generally inert toward conventional Mg, Zn, or Mn(II) reagents. Although the alkali metal is an essential component of these new complex metalators, interestingly, the less electropositive, less polar nonalkali metal [Mg, Zn, or Mn(II)] actually carries out the deprotonation. We view this unique behavior as a mixed-metal synergic effect: intramolecular communication through metal - ligand-metal bridges directs special regioselectivities or polydeprotonations. We demonstrate structurally defined alkali-metal-mediated magnesiations (AMMMg), zincations (AMMZn), and manganations [AMMMn(II)] of representative aromatic substrates (including benzene, toluene, anisole, and ferrocene). In addition, we present remarkable meta-orientated metalations of toluene and N,N-dimethylaniline. We also review 2-fold metalations of arenes, in which an arenediide guest is encapsulated within a 12-atom polymetallic cationic (NaNNaNMgN)(2) host ring to form inverse crown structures. Furthermore, using X-ray crystallography of a turbo-Grignard reagent, we establish a link between our complex metalators and turbo-Grignard reagents. Armed with this accruing knowledge of complex metalators, we think rapid progress in "low polarity metalation" should now be possible. The greatest remaining challenge is to develop methodologies that shift these processes from stoichiometric reactions into more economical catalytic ones.
LanguageEnglish
Pages743-755
Number of pages12
JournalAccounts of Chemical Research
Volume42
Issue number6
DOIs
Publication statusPublished - Jun 2009

Fingerprint

Alkali Metals
Metals
Carbon
Toluene
Lithium
Regioselectivity
Deprotonation
X ray crystallography
Organometallics
Substrates
Benzene
Amides
Functional groups
Hydrogen bonds
Salts
2,2,6,6-tetramethylpiperidide
Ligands
Atoms
Molecules
Kinetics

Keywords

  • directed ortho metalation
  • inverse crowns
  • amide
  • chemistry
  • magnesium
  • deprotonation
  • manganation

Cite this

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title = "Avant-garde metalating agents: Structural basis of alkali-metal-mediated metalation",
abstract = "Metalation, one of the most useful and widely used synthetic methodologies, transforms a relatively inert carbon-hydrogen bond to a more labile carbon-metal bond. Until recently, most organometallic reagents that facilitate this process have combined strongly electropositive metals, such as lithium, with organic reagents to form highly polar and, by implication, highly reactive carbon-metal bonds. For example, the alkyllithium reagents and bulky lithium amides that are commonly employed for this purpose can suffer from low functional group tolerance. Lithio-products of these reactions generally have low kinetic stabilities. More recently, several groups around the world have pioneered alternative metalation reagents, complex metalators, which can be interpreted as composite molecules or mixtures made up of two or more distinct compound types. Several examples include magnesiate complexes, Lochmann-Schlosser superbases, Kondo and Uchiyama's 2,2,6,6-tetramethylpiperidide (TMP)-zincate complexes, and Knochel's turbo-Grignard and related salt-supported reagents. This Account describes our rational development of novel complex metalators based on existing structural templates and designed to execute alkali-metal-mediated metalations (AMMMs). By changing the nonalkali metal in these structures, we have produced tailor-made dianionic-dicationic structures such as [(TMEDA) center dot Na(mu-TMP)(mu-Bu-n)Mg(TMP)], [(TMEDA) center dot Na(mu-TMP)(mu-Bu-t)Zn(Bu-t)], and [(TMEDA) center dot Li(mu-TMP)Mn(CH2SiMe3)(2)] (TMEDA = N,N,N',N'-tetramethylethylenediamine). These compounds can perform unprecedented magnesiations, zincations, or manganations on aromatic substrates that are generally inert toward conventional Mg, Zn, or Mn(II) reagents. Although the alkali metal is an essential component of these new complex metalators, interestingly, the less electropositive, less polar nonalkali metal [Mg, Zn, or Mn(II)] actually carries out the deprotonation. We view this unique behavior as a mixed-metal synergic effect: intramolecular communication through metal - ligand-metal bridges directs special regioselectivities or polydeprotonations. We demonstrate structurally defined alkali-metal-mediated magnesiations (AMMMg), zincations (AMMZn), and manganations [AMMMn(II)] of representative aromatic substrates (including benzene, toluene, anisole, and ferrocene). In addition, we present remarkable meta-orientated metalations of toluene and N,N-dimethylaniline. We also review 2-fold metalations of arenes, in which an arenediide guest is encapsulated within a 12-atom polymetallic cationic (NaNNaNMgN)(2) host ring to form inverse crown structures. Furthermore, using X-ray crystallography of a turbo-Grignard reagent, we establish a link between our complex metalators and turbo-Grignard reagents. Armed with this accruing knowledge of complex metalators, we think rapid progress in {"}low polarity metalation{"} should now be possible. The greatest remaining challenge is to develop methodologies that shift these processes from stoichiometric reactions into more economical catalytic ones.",
keywords = "directed ortho metalation, inverse crowns, amide, chemistry, magnesium, deprotonation, manganation",
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year = "2009",
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language = "English",
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Avant-garde metalating agents: Structural basis of alkali-metal-mediated metalation. / Mulvey, Robert E.

In: Accounts of Chemical Research , Vol. 42, No. 6, 06.2009, p. 743-755.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Avant-garde metalating agents: Structural basis of alkali-metal-mediated metalation

AU - Mulvey, Robert E.

PY - 2009/6

Y1 - 2009/6

N2 - Metalation, one of the most useful and widely used synthetic methodologies, transforms a relatively inert carbon-hydrogen bond to a more labile carbon-metal bond. Until recently, most organometallic reagents that facilitate this process have combined strongly electropositive metals, such as lithium, with organic reagents to form highly polar and, by implication, highly reactive carbon-metal bonds. For example, the alkyllithium reagents and bulky lithium amides that are commonly employed for this purpose can suffer from low functional group tolerance. Lithio-products of these reactions generally have low kinetic stabilities. More recently, several groups around the world have pioneered alternative metalation reagents, complex metalators, which can be interpreted as composite molecules or mixtures made up of two or more distinct compound types. Several examples include magnesiate complexes, Lochmann-Schlosser superbases, Kondo and Uchiyama's 2,2,6,6-tetramethylpiperidide (TMP)-zincate complexes, and Knochel's turbo-Grignard and related salt-supported reagents. This Account describes our rational development of novel complex metalators based on existing structural templates and designed to execute alkali-metal-mediated metalations (AMMMs). By changing the nonalkali metal in these structures, we have produced tailor-made dianionic-dicationic structures such as [(TMEDA) center dot Na(mu-TMP)(mu-Bu-n)Mg(TMP)], [(TMEDA) center dot Na(mu-TMP)(mu-Bu-t)Zn(Bu-t)], and [(TMEDA) center dot Li(mu-TMP)Mn(CH2SiMe3)(2)] (TMEDA = N,N,N',N'-tetramethylethylenediamine). These compounds can perform unprecedented magnesiations, zincations, or manganations on aromatic substrates that are generally inert toward conventional Mg, Zn, or Mn(II) reagents. Although the alkali metal is an essential component of these new complex metalators, interestingly, the less electropositive, less polar nonalkali metal [Mg, Zn, or Mn(II)] actually carries out the deprotonation. We view this unique behavior as a mixed-metal synergic effect: intramolecular communication through metal - ligand-metal bridges directs special regioselectivities or polydeprotonations. We demonstrate structurally defined alkali-metal-mediated magnesiations (AMMMg), zincations (AMMZn), and manganations [AMMMn(II)] of representative aromatic substrates (including benzene, toluene, anisole, and ferrocene). In addition, we present remarkable meta-orientated metalations of toluene and N,N-dimethylaniline. We also review 2-fold metalations of arenes, in which an arenediide guest is encapsulated within a 12-atom polymetallic cationic (NaNNaNMgN)(2) host ring to form inverse crown structures. Furthermore, using X-ray crystallography of a turbo-Grignard reagent, we establish a link between our complex metalators and turbo-Grignard reagents. Armed with this accruing knowledge of complex metalators, we think rapid progress in "low polarity metalation" should now be possible. The greatest remaining challenge is to develop methodologies that shift these processes from stoichiometric reactions into more economical catalytic ones.

AB - Metalation, one of the most useful and widely used synthetic methodologies, transforms a relatively inert carbon-hydrogen bond to a more labile carbon-metal bond. Until recently, most organometallic reagents that facilitate this process have combined strongly electropositive metals, such as lithium, with organic reagents to form highly polar and, by implication, highly reactive carbon-metal bonds. For example, the alkyllithium reagents and bulky lithium amides that are commonly employed for this purpose can suffer from low functional group tolerance. Lithio-products of these reactions generally have low kinetic stabilities. More recently, several groups around the world have pioneered alternative metalation reagents, complex metalators, which can be interpreted as composite molecules or mixtures made up of two or more distinct compound types. Several examples include magnesiate complexes, Lochmann-Schlosser superbases, Kondo and Uchiyama's 2,2,6,6-tetramethylpiperidide (TMP)-zincate complexes, and Knochel's turbo-Grignard and related salt-supported reagents. This Account describes our rational development of novel complex metalators based on existing structural templates and designed to execute alkali-metal-mediated metalations (AMMMs). By changing the nonalkali metal in these structures, we have produced tailor-made dianionic-dicationic structures such as [(TMEDA) center dot Na(mu-TMP)(mu-Bu-n)Mg(TMP)], [(TMEDA) center dot Na(mu-TMP)(mu-Bu-t)Zn(Bu-t)], and [(TMEDA) center dot Li(mu-TMP)Mn(CH2SiMe3)(2)] (TMEDA = N,N,N',N'-tetramethylethylenediamine). These compounds can perform unprecedented magnesiations, zincations, or manganations on aromatic substrates that are generally inert toward conventional Mg, Zn, or Mn(II) reagents. Although the alkali metal is an essential component of these new complex metalators, interestingly, the less electropositive, less polar nonalkali metal [Mg, Zn, or Mn(II)] actually carries out the deprotonation. We view this unique behavior as a mixed-metal synergic effect: intramolecular communication through metal - ligand-metal bridges directs special regioselectivities or polydeprotonations. We demonstrate structurally defined alkali-metal-mediated magnesiations (AMMMg), zincations (AMMZn), and manganations [AMMMn(II)] of representative aromatic substrates (including benzene, toluene, anisole, and ferrocene). In addition, we present remarkable meta-orientated metalations of toluene and N,N-dimethylaniline. We also review 2-fold metalations of arenes, in which an arenediide guest is encapsulated within a 12-atom polymetallic cationic (NaNNaNMgN)(2) host ring to form inverse crown structures. Furthermore, using X-ray crystallography of a turbo-Grignard reagent, we establish a link between our complex metalators and turbo-Grignard reagents. Armed with this accruing knowledge of complex metalators, we think rapid progress in "low polarity metalation" should now be possible. The greatest remaining challenge is to develop methodologies that shift these processes from stoichiometric reactions into more economical catalytic ones.

KW - directed ortho metalation

KW - inverse crowns

KW - amide

KW - chemistry

KW - magnesium

KW - deprotonation

KW - manganation

UR - http://dx.doi.org/10.1021/ar800254y

U2 - 10.1021/ar800254y

DO - 10.1021/ar800254y

M3 - Article

VL - 42

SP - 743

EP - 755

JO - Accounts of Chemical Research

T2 - Accounts of Chemical Research

JF - Accounts of Chemical Research

SN - 0001-4842

IS - 6

ER -