Hauser bases, also called magnesium amide bases, are
magnesium
Magnesium is a chemical element with the symbol Mg and atomic number 12. It is a shiny gray metal having a low density, low melting point and high chemical reactivity. Like the other alkaline earth metals (group 2 of the periodic ...
compounds used in
organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the science, scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clay ...
as
bases for
metalation reactions. These compounds were first described by
Charles R. Hauser in 1947. Compared with
organolithium reagent
In organometallic chemistry, organolithium reagents are chemical compounds that contain carbon–lithium (C–Li) bonds. These reagents are important in organic synthesis, and are frequently used to transfer the organic group or the lithium atom ...
s, the magnesium compounds have more covalent, and therefore less reactive, metal-ligand bonds. Consequently, they display a higher degree of functional group tolerance and a much greater
chemoselectivity
Chemoselectivity is the preferential outcome of a chemical reaction over a set of possible alternative reactions.
In another definition, chemoselectivity refers to the selective reactivity of one functional group in the presence of others; often ...
. Generally, Hauser bases are used at room temperature while reactions with organolithium reagents are performed at low temperatures, commonly at −78 °C.
Structure
Solid state structure
Like all
Grignard dimers, Hauser bases derived from
2,2,6,6-tetramethylpiperidine (TMP)
and
HMDS HMDS may refer to:
* either of two related reagents in organometallic chemistry:
** Hexamethyldisilazane ( CH3)3Sisub>2NH)
** Hexamethyldisilazide ( CH3)3Sisub>2NM)
*** M = Li as in Lithium bis(trimethylsilyl)amide
Lithium bis(trimethylsilyl)a ...
are bridged by halides in the solid state. In contrast to Grignard reagents, dimeric amido bridged Hauser bases exist, too. All have one in common: they are bridged by less bulky amido ligands such as Et
2N−,
Ph
3P=N− and
''i''Pr2N−. The displacement to halide bridges may be a result of the bulky groups on the amide ligand.
Solution structure
Although there is a great deal of information on the utility of these reagents, very little is known regarding the nature of Hauser bases in solution. One reason for that lack of information is that Hauser bases show a complex behaviour in solution. It was proposed that it could be similar to the
Schlenk equilibrium Schlenk can refer to:
People
* Wilhelm Schlenk (1879-1943), German chemist
In chemistry
* Schlenk flask
* Schlenk line
The Schlenk line (also vacuum gas manifold) is a commonly used chemistry apparatus developed by Wilhelm Schlenk. It consist ...
of
Grignard reagents
A Grignard reagent or Grignard compound is a chemical compound with the general formula , where X is a halogen and R is an organic group, normally an alkyl or aryl. Two typical examples are methylmagnesium chloride and phenylmagnesium bromide ...
in ether solution, where more than one magnesium containing species exists.
[Neufeld, Roman.]
''DOSY External Calibration Curve Molecular Weight Determination as a Valuable Methodology in Characterizing Reactive Intermediates in Solution.''
In: ''eDiss, Georg-August-Universität Göttingen.'' 2016. In 2016, ''Neufeld et al.'' showed by
diffusion-ordered spectroscopy (DOSY) that the solution structure of ''i''Pr
2NMgCl is best represented by the common Schlenk equilibrium:
:''i''Pr
2NMgCl (A) (''i''Pr
2N)
2Mg (B) + MgCl
2
This equilibrium is highly temperature dependent with
heteroleptic
In inorganic chemistry, a homoleptic chemical compound is a metal compound with all ligands identical. The term uses the " homo-" prefix to indicate that something is the same for all. Any metal species which has more than one type of ligand is he ...
(A) to be the main species at high temperatures and
homoleptic
In inorganic chemistry, a homoleptic chemical compound is a metal compound with all ligands identical. The term uses the " homo-" prefix to indicate that something is the same for all. Any metal species which has more than one type of ligand is he ...
(B) at low temperatures.
Dimeric species with bridging chlorides and amides are also present in the THF solution, although alkyl magnesium chlorides do not dimerize in THF. At low temperatures, where an excess of MgCl
2 is available MgCl
2 co-coordinated species are present in solution, too.
Preparation
The Hauser bases are prepared by mixing an amine and a
Grignard reagent.
:R
2NH + R′MgX → R
2NMgX + R′H X = Cl, Br, I
Uses
Hauser bases are generally used as
metalation Metalation (Alt. spelling: Metallation) is a chemical reaction that forms a bond to a metal. This reaction usually refers to the replacement of a halogen atom in an organic molecule with a metal atom, resulting in an organometallic compound. In th ...
reagents, like
organolithiums or
metal amides Metal amides (systematic name metal azanides) are a class of coordination compounds composed of a metal center with amide ligands of the form NR2−. Amide ligands have two electron pairs available for bonding. In principle, they can be terminal or ...
.
The breakthrough in synthetic protocols of Hauser bases culminates in the 1980s and 1990s. Eaton and coworkers showed that ''i''Pr
2NMgBr selectively magnesiate carboxamides in ortho position.
Later, Kondo, Sakamo and co-workers reported the utility of ''i''Pr
2NMgX (X = Cl, Br) as selective deprotonation reagents (exclusively at the 2-position) for heterocyclic thiophene and phenylsulphonyl-substituted indoles.

A major disadvantage of Hauser bases is their poor solubility in THF. In consequence, the metalation rates are slow and a large excess of base is required (mostly 10 equiv.). This circumstance complicates the functionalization of the metaled intermediate with an electrophile.
Better solubility and reactivity can be achieved by adding stoichiometric amounts of LiCl to the Hauser base. These so-called
''Turbo''-Hauser bases like e.g. TMPMgCl·LiCl and ''i''Pr
2NMgCl·LiCl are commercially available and show an enhanced kinetic basicity, excellent regioselectivity and high functional group tolerance for a large number of
aromatic
In chemistry, aromaticity is a chemical property of cyclic (ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to sat ...
and
heteroaromatic
In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...
substrates.
Commonly used Hauser bases
*''i''Pr
2NMgX
*TMPMgX (
TMP TMP can refer to any of the following:
Chemistry
* 2,2,6,6-Tetramethylpiperidine, an organic chemistry reagent
* Thymidine monophosphate, a nucleotide
* Trimethoprim, an antibiotic
* Trimethyl phosphate, a solvent
* Trimethylolpropane, a precurso ...
= 2,2,6,6,tetramethylpiperidino, X= Cl, Br)
References
{{Reflist
Magnesium compounds
*