Structural basis for regioisomerization in the alkali-metal-mediated zincation (AMMZn) of trifluoromethyl benzene by isolation of kinetic and thermodynamic intermediates

David R. Armstrong, Victoria L. Blair, William Clegg, Sophie H. Dale, Joaquin Garcia-Alvarez, Gordon W. Honeyman, Eva Hevia, Robert E. Mulvey, Luca Russo

Research output: Contribution to journalArticle

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Abstract

Performed with a desire to advance knowledge of the structures and mechanisms governing alkali-metal-mediated zincation, this study monitors the reaction between the TMP-dialkylzincate reagent RTMEDA)Na(TMP)(Bu-t)Zn(Bu-t)] 1 and trifluoromethyl benzene C6H5CF3 2. A complicated mixture of products is observed at room temperature. X-ray crystallography has identified two of these products as ortho- and meta-regioisomers of heterotrianionic RTMEDA)Na(TMP)(C6H4-CF3)Zn(Bu-t)], 3-ortho and 3-meta, respectively. Multinuclear NMR data of the bulk crystalline product confirm the presence of these two regioisomers as well as a third isomer, 3-para, in a respective ratio of 20:11:1, and an additional product 4, which also exhibits ortho-zincation of the aryl substrate. Repeating the reaction at 0 C gave exclusively 4, which was crystallographically characterized as [{(TMEDA)(2)Na}(+)(Zn(C6H4-CF3)(Bu-t)(2)}(-)}. Mimicking the original room-temperature reaction, this kinetic product was subsequently reacted with TMP(H) to afford a complicated mixture of products, including significantly the three regioisomers of 3. Surprisingly, 4 adopts a solvent-separated ion pair arrangement in contrast to the contacted ion variants of 3-ortho and 3-meta. Aided by DFT calculations on model systems, discussion focuses on the different basicities, amido or alkyl, and steps, exhibited in these reactions, and how the structures and bonding within these isolated key metallic intermediates (prior to any electrophilic interception step), specifically the interactions involving the alkali metal, influence the regioselectivity of the Zn-H exchange process.

LanguageEnglish
Pages9480-9487
Number of pages8
JournalJournal of the American Chemical Society
Volume132
Issue number27
DOIs
Publication statusPublished - 14 Jul 2010

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Thymidine Monophosphate
Alkali Metals
Alkali metals
Benzene
Thermodynamics
Regioselectivity
Kinetics
X ray crystallography
Ions
Alkalinity
Discrete Fourier transforms
Isomers
Ion exchange
Nuclear magnetic resonance
Crystalline materials
Biomolecular Nuclear Magnetic Resonance
Temperature
X Ray Crystallography
Substrates

Keywords

  • directed ortho-metalation
  • tertiary aromatic amide
  • cation-pi interactions
  • tmp-zincate
  • deprotonative metalation
  • functionalized aromatics
  • chemoselective base
  • reaction pathway
  • insights
  • alkyl

Cite this

Armstrong, David R. ; Blair, Victoria L. ; Clegg, William ; Dale, Sophie H. ; Garcia-Alvarez, Joaquin ; Honeyman, Gordon W. ; Hevia, Eva ; Mulvey, Robert E. ; Russo, Luca. / Structural basis for regioisomerization in the alkali-metal-mediated zincation (AMMZn) of trifluoromethyl benzene by isolation of kinetic and thermodynamic intermediates. In: Journal of the American Chemical Society. 2010 ; Vol. 132, No. 27. pp. 9480-9487.
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Structural basis for regioisomerization in the alkali-metal-mediated zincation (AMMZn) of trifluoromethyl benzene by isolation of kinetic and thermodynamic intermediates. / Armstrong, David R.; Blair, Victoria L.; Clegg, William; Dale, Sophie H.; Garcia-Alvarez, Joaquin; Honeyman, Gordon W.; Hevia, Eva; Mulvey, Robert E.; Russo, Luca.

In: Journal of the American Chemical Society, Vol. 132, No. 27, 14.07.2010, p. 9480-9487.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Structural basis for regioisomerization in the alkali-metal-mediated zincation (AMMZn) of trifluoromethyl benzene by isolation of kinetic and thermodynamic intermediates

AU - Armstrong, David R.

AU - Blair, Victoria L.

AU - Clegg, William

AU - Dale, Sophie H.

AU - Garcia-Alvarez, Joaquin

AU - Honeyman, Gordon W.

AU - Hevia, Eva

AU - Mulvey, Robert E.

AU - Russo, Luca

PY - 2010/7/14

Y1 - 2010/7/14

N2 - Performed with a desire to advance knowledge of the structures and mechanisms governing alkali-metal-mediated zincation, this study monitors the reaction between the TMP-dialkylzincate reagent RTMEDA)Na(TMP)(Bu-t)Zn(Bu-t)] 1 and trifluoromethyl benzene C6H5CF3 2. A complicated mixture of products is observed at room temperature. X-ray crystallography has identified two of these products as ortho- and meta-regioisomers of heterotrianionic RTMEDA)Na(TMP)(C6H4-CF3)Zn(Bu-t)], 3-ortho and 3-meta, respectively. Multinuclear NMR data of the bulk crystalline product confirm the presence of these two regioisomers as well as a third isomer, 3-para, in a respective ratio of 20:11:1, and an additional product 4, which also exhibits ortho-zincation of the aryl substrate. Repeating the reaction at 0 C gave exclusively 4, which was crystallographically characterized as [{(TMEDA)(2)Na}(+)(Zn(C6H4-CF3)(Bu-t)(2)}(-)}. Mimicking the original room-temperature reaction, this kinetic product was subsequently reacted with TMP(H) to afford a complicated mixture of products, including significantly the three regioisomers of 3. Surprisingly, 4 adopts a solvent-separated ion pair arrangement in contrast to the contacted ion variants of 3-ortho and 3-meta. Aided by DFT calculations on model systems, discussion focuses on the different basicities, amido or alkyl, and steps, exhibited in these reactions, and how the structures and bonding within these isolated key metallic intermediates (prior to any electrophilic interception step), specifically the interactions involving the alkali metal, influence the regioselectivity of the Zn-H exchange process.

AB - Performed with a desire to advance knowledge of the structures and mechanisms governing alkali-metal-mediated zincation, this study monitors the reaction between the TMP-dialkylzincate reagent RTMEDA)Na(TMP)(Bu-t)Zn(Bu-t)] 1 and trifluoromethyl benzene C6H5CF3 2. A complicated mixture of products is observed at room temperature. X-ray crystallography has identified two of these products as ortho- and meta-regioisomers of heterotrianionic RTMEDA)Na(TMP)(C6H4-CF3)Zn(Bu-t)], 3-ortho and 3-meta, respectively. Multinuclear NMR data of the bulk crystalline product confirm the presence of these two regioisomers as well as a third isomer, 3-para, in a respective ratio of 20:11:1, and an additional product 4, which also exhibits ortho-zincation of the aryl substrate. Repeating the reaction at 0 C gave exclusively 4, which was crystallographically characterized as [{(TMEDA)(2)Na}(+)(Zn(C6H4-CF3)(Bu-t)(2)}(-)}. Mimicking the original room-temperature reaction, this kinetic product was subsequently reacted with TMP(H) to afford a complicated mixture of products, including significantly the three regioisomers of 3. Surprisingly, 4 adopts a solvent-separated ion pair arrangement in contrast to the contacted ion variants of 3-ortho and 3-meta. Aided by DFT calculations on model systems, discussion focuses on the different basicities, amido or alkyl, and steps, exhibited in these reactions, and how the structures and bonding within these isolated key metallic intermediates (prior to any electrophilic interception step), specifically the interactions involving the alkali metal, influence the regioselectivity of the Zn-H exchange process.

KW - directed ortho-metalation

KW - tertiary aromatic amide

KW - cation-pi interactions

KW - tmp-zincate

KW - deprotonative metalation

KW - functionalized aromatics

KW - chemoselective base

KW - reaction pathway

KW - insights

KW - alkyl

U2 - 10.1021/ja1038598

DO - 10.1021/ja1038598

M3 - Article

VL - 132

SP - 9480

EP - 9487

JO - Journal of the American Chemical Society

T2 - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 27

ER -