Turbo home bases

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In Turbo -Hauserbasen is Magnesiumamidhalogenide ( Hauser bases ), the stoichiometric amounts of lithium chloride contained. These mixed Mg / Li - amides of type R 2 find NMgCl⋅LiCl in organic chemistry as non-nucleophilic bases for metalation of aromatic and heteroaromatic substrates use. Compared to their lithium chloride-free ancestors, Turbo Hauserbases have increased kinetic basicity , excellent regioselectivity , high tolerance towards functional groups and better solubility .

presentation

Typically, Turbo Hauserbases are made by reacting an amine with a Grignard reagent or by mixing a lithium amide with stoichiometric amounts of MgCl 2 .

Typical representations of turbo house bases

The most common Turbo Hauserbase include i Pr 2 NMgCl LiCl ( i Pr Turbo Hauserbase) and TMPMgClLiCl (TMP Turbo Hauserbase, also known as Knochel Hauserbase (TMP = 2,2,6,6, tetramethylpiperidino )).

structure

So far, not many structures of turbo home bases are known. In general, however, it can be said that they show a complex temperature and concentration dependence in solution. For this reason, it is not easy to crystallize house bases and their turbo variants.

Solid structure

The i Pr Turbo Hauserbase crystallizes as a dimeric , amido-bridged contact ion pair . The TMP ligand, however, has a higher steric demand , which prevents dimerization. For this reason the TMP Turbo Hauserbase crystallizes as a monomeric contact ion pair. In both cases the lithium chloride coordinates to the magnesium amide.

i Pr Turbo Hauserbase in the solid state
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TMP turbo house base in the solid state
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Structure in solution

Although the use of turbo home bases is well known, knowledge of their behavior in solution is limited. One reason for this lack of information lies in the complex behavior that they exhibit in solution. In 2016, Neufeld et al. using Diffusion-Ordered Spectroscopy (DOSY) show that the dimeric solid-state structure [ i Pr 2 NMgCl·LiCl] 2 is also present in solution at room temperatures and high concentrations (0.6 M) . At lower concentrations, however, the equilibrium is on the side of the monomeric species. Both the monomeric and dimeric species show co-coordination of the lithium chloride. At temperatures below −50 ° C, the lithium chloride is split off from the magnesium amide, so that a stable [LiCl] 2 dimer is present that is solvated by four THF molecules.

The behavior of the i Pr Turbo Hauserbase in a THF solution at high temperatures (left) and low temperatures (right)

In the case of the TMP Turbo Hauserbase, however, the solid structure is almost completely present in THF solution, regardless of the concentration and temperature. Due to the high steric demand of the TMP ligand and its flexible rotation in solution, the THF molecule is split off from the magnesium cation, which leads to a free coordination site on the same and could explain the increased reactivity and selectivity of TMPMgCl·LiCl.

The behavior of the TMP Turbo Hauserbase in a THF solution

Knochel et al. have suggested that the lithium chloride increase the reactivity of Turbo -Grignard of the type RMgCl·LiCl (R = alkyl , aryl or vinyl ) by giving the reactive bimetallic monomer a magnesia character in the sense of a solvent-separated ion pair [Li (THF) 4 ] + [RMg (THF) Cl 2 ] - give. In the case of the above-mentioned Turbo Hauser bases, in which the alkyl group of the Grignard reagent was replaced by an amido group (R = R ' 2 N - ), this hypothesis could not be confirmed, since [Li (THF) 4 ] + was not observed .

Reactivity

In contrast to Turbo Grignard compounds , which are used for highly efficient Br / Mg exchange reactions, Turbo Hauserbases are used as an effective deprotonation reagent for functionalized aromatics. After the deprotonation, the intermediate product (a Turbo Grignard) can be selectively functionalized by the addition of an electrophile (for example I 2 or -CHO ).

General scheme of a reaction with a turbo Hauserbase (FG = functional group, DG = directing group (for example CO 2 R , CN , COR ))
Deprotonation of an aryl with functional groups that are sensitive to bases and subsequent functionalization with I 2 leads to the benzene derivative shown in 88% yield
The selective methylation of a furan and subsequent addition of an aldehyde leads to the alcohol shown in 83% yield.

Like organolithium compounds, Turbo Hauserbases are used as metalation and deprotonation reagents . However, many lithiated compounds are only stable at low temperatures (e.g. −78 ° C) or competing addition reactions such as the Chichibabin reaction can occur. In contrast, the magnesium compounds have more covalent and therefore less reactive metal-ligand bonds. In addition, the entire magnesium amide complex is stabilized by the lithium chloride. With turbo house bases, this leads to a higher tolerance towards functional groups and a higher chemoselectivity at high and low temperatures.

i Pr 2 NMgCl·LiCl partially shows a different reactivity compared to TMPMgCl·LiCl. Sun showed Armstrong et al. that the TMP Turbo Hauser base metalates ethyl 3-chlorobenzoate without any problems in the C2 position, whereas the same reaction with the i Pr Turbo Hauser does not lead to any metalation. In contrast, an addition-elimination reaction occurs.

The different reactivity of TMPMgCl·LiCl and i Pr 2 NMgCl·LiCl

Another difference could be found by Krasovskiy et al. shown in the deprotonation of isoquinoline in a THF solution. While the reaction with i Pr 2 NMgCl·LiCl takes 12 hours and 2 equivalents of the Turbo Hauser base, the reaction with TMPMgCl·LiCl only takes two hours and 1.1 equivalents.

The different reactivity of i Pr 2 NMgCl·LiCl and TMPMgCl·LiCl towards isoquinoline

On the one hand, the different reactivity to the higher kinetic basicity of the TMP compound compared to the homologous i Pr- Turbo Hauserbase can be explained. On the other hand, the different behavior of the two connections in solution probably also plays a role (see previous chapter). In organolithium chemistry, for example, monomeric species show the highest kinetic activity. Analogously, this could explain why the monomeric TMP- Turbo Hauserbase reacts significantly faster than the dimeric i Pr-substituted one.

Neufeld et al. have additionally suggested that the high regioselectivity of the ortho -deprotonation reactions in TMPMgCl·LiCl is related to the spatial proximity in the transition-state complex between the bimetallic aggregate and the functionalized (hetero) aromatic substrate.

Proposed transition states that illustrate the spatial proximity in TMPMgCl·LiCl mediated reactions

Individual evidence

  1. ↑ a b c d Arkady Krasovskiy, Valeria Krasovskaya, Paul Knochel: Mixed Mg / Li Amides of the Type R2NMgCl ⋅ LiCl as Highly Efficient Bases for the Regioselective Generation of Functionalized Aryl and Heteroaryl Magnesium Compounds . In: Angewandte Chemie International Edition . tape 45 , no. 18 , April 28, 2006, ISSN  1433-7851 , p. 2958-2961 , doi : 10.1002 / anie.200504024 .
  2. ↑ New Reagents for Selective Metalation, deprotonation, and Additions. Retrieved October 27, 2019 .
  3. ↑ 2,2,6,6-Tetramethylpiperidinylmagnesium chloride lithium chloride complex solution 703540. Retrieved October 27, 2019 .
  4. ^ A b Neufeld, R .: DOSY External Calibration Curve Molecular Weight Determination as a Valuable Methodology in Characterizing Reactive Intermediates in Solution. In: eDiss, Georg-August-Universität Göttingen. 2016.
  5. ^ A b David R. Armstrong, Pablo García-Álvarez, Alan R. Kennedy, Robert E. Mulvey, John A. Parkinson: Diisopropylamide and TMP Turbo-Grignard Reagents: A Structural Rationale for their Contrasting Reactivities . In: Angewandte Chemie International Edition . tape 49 , no. 18 , April 19, 2010, pp. 3185-3188 , doi : 10.1002 / anie.201000539 .
  6. ^ Pablo García-Álvarez, David V. Graham, Eva Hevia, Alan R. Kennedy, Jan Klett: Unmasking Representative Structures of TMP-Active Hauser and Turbo-Hauser Bases . In: Angewandte Chemie International Edition . tape 47 , no. 42 , October 6, 2008, p. 8079-8081 , doi : 10.1002 / anie.200802618 .
  7. ↑ Roman Neufeld, Dietmar Stalke: Accurate molecular weight determination of small molecules via DOSY NMR by using external calibration curves with normalized diffusion Coefficients . In: Chemical Science . tape 6 , no. 6 , 2015, ISSN  2041-6520 , p. 3354–3364 , doi : 10.1039 / C5SC00670H , PMID 29142693 , PMC 5656982 (free full text).
  8. ^ Roman Neufeld, Thorsten L. Teuteberg, Regine Herbst-Irmer, Ricardo A. Mata, Dietmar Stalke: Solution Structures of Hauser Base i Pr 2 NMgCl and Turbo-Hauser Base i Pr 2 NMgCl·LiCl in THF and the Influence of LiCl on the Schlenk Equilibrium . In: Journal of the American Chemical Society . tape 138 , no. 14 , April 13, 2016, ISSN  0002-7863 , p. 4796-4806 , doi : 10.1021 / jacs.6b00345 .
  9. ^ Hans J. Reich, Joseph P. Borst, Robert R. Dykstra, Patrick D. Green: A nuclear magnetic resonance spectroscopic technique for the characterization of lithium ion pair structures in THF and THF / HMPA solution . In: Journal of the American Chemical Society . tape 115 , no. September 19 , 1993, ISSN  0002-7863 , pp. 8728-8741 , doi : 10.1021 / ja00072a028 .
  10. ^ A b Roman Neufeld, Dietmar Stalke: Solution Structure of Turbo-Hauser Base TMPMgCl ⋅ LiCl in [D 8] THF . In: Chemistry - A European Journal . tape 22 , no. 36 , August 26, 2016, p. 12624-12628 , doi : 10.1002 / chem . 201601494 .
  11. ^ Arkady Krasovskiy, Bernd F. Straub, Paul Knochel: Highly Efficient Reagents for Br / Mg Exchange . In: Angewandte Chemie International Edition . tape 45 , no. 1 , January 2006, ISSN  1433-7851 , p. 159–162 , doi : 10.1002 / anie.200502220 .
  12. ↑ Chao Feng, Drew W. Cunningham, Quinn T. Easter, Suzanne A. Blum: Role of LiCl in Generating Soluble Organozinc Reagents . In: Journal of the American Chemical Society . tape 138 , no. 35 , September 7, 2016, ISSN  0002-7863 , p. 11156-11159 , doi : 10.1021 / jacs.6b08465 .
  13. ↑ Arkady Krasovskiy, Paul Knochel: A LiCl-Mediated Br / Mg Exchange Reaction for the Preparation of Functionalized Aryl- and Heteroarylmagnesium Compounds from Organic Bromides . In: Angewandte Chemie International Edition . tape 43 , no. 25 , June 21, 2004, ISSN  1433-7851 , p. 3333-3336 , doi : 10.1002 / anie.200454084 .
  14. ^ Robert Li-Yuan Bao, Rong Zhao, Lei Shi: Progress and developments in the turbo Grignard reagent i-PrMgCl LiCl: a ten-year journey . In: Chemical Communications . tape 51 , no. 32 , 2015, ISSN  1359-7345 , p. 6884-6900 , doi : 10.1039 / C4CC10194D .