Hoffmann test

The application of the Hoffmann test """ " confirms configurational stability of these lithium compounds on the microscopic scale at low temperature, indicating that rather thermodynamic than dynamic kinetic resolution is operating at the reaction conditions " . 

The TMEDA complex of a-lithiobenzyl iV,iV-diisopropylcarbamate was found to be configurationally stable on the microscopical scale in the Hoffmann test . The (—)-sparteine complex 222 has moderate configurational stability on the macroscopic scale, which could not been brought to useful selectivities in substitution reactions . As... 

An interesting stereochemical situation was found for the lithium-)—)-sparteine complex derived from o-ethyl-A,A-diisopropylcarboxamide 267 (equation 65) . Control experiments, involving lithiodestannylation experiments and the Hoffmann test, led to the conclusion that 268/ep/-268 are configurationally unstable at —78 °C and the e.r. in 269 is determined by a dynamic kinetic resolution of the rapidly interconverting intermediates . It is noteworthy that the configuration is inverted by using tosylates . 

When they subjected the allenylzinc reagent to the Hoffmann test for configurational stability,29 Poisson, Chemla and Normant found that at — 50 °C, racemization does not occur at a significant rate (equation 36)30,31. Accordingly, when the racemic allenylzinc reagent was added slowly to the /V-benzy limine of (R)-mandehc aldehyde at — 50 °C, a 1 1 mixture of the anti,syn and anti,anti adducts was isolated in 65% yield. However, when the addition process was reversed, a 3 1 mixture favoring the matched anti,anti adduct was formed in 53% yield, suggestive of a partial kinetic resolution. 

The Hoffmann test. The Hoffmann test,4 while not quantitative, gives a qualitative guide to the configurational stability of an organolithium on the timescale of its addition to an electrophile. 

In some cases the Hoffmann test fails to be useful. For example, the lithiated amine 9 gives a 50 50 mixture of diastereoisomers 10 and 11 on reaction with ( )-6. No useful information can be drawn in such an instance.6... 

Beak has described what he calls the poor man s Hoffmann test because is does not require use of an enantiomerically pure electrophile.7 This version of the Test also relies on a rate difference between diastereoisomeric transition states, but it quantifies the rate difference by the outcome of a reaction in which enantiomeric organolithiums compete for a deficit of... 

This is about the bottom end of the next timescale - the microscopic timescale - which is associated with the rate at which organolithium nucleophiles will add to electrophiles (usually a matter of seconds at the most). Configurational stability on the microscopic timescale is studied by the Hoffmann test, or by formation of organolithiums in the presence of electrophiles (such as Me3SiCl) with which they react immediately - in situ quench conditions. 

Nonetheless, secondary benzylic a-alkoxyorganolithiums may have configurational stability on the microscopic timescale, as indicated by a Hoffmann test.6 As discussed above (section 5.1.1), the lithiated benzyicarbamate 5 is configurationally stable by the test. A Hoffmann test on 99, the tertiary benzylic analogue of 5, confirmed the configurational stability previously demonstrated by Hoppe.51 52... 

By NMR, Hoffmann determined the configurational stability of a simple lithiated benzylamine 192 to be 9.0 kcal mol"1.2 However, an attempted Hoffmann test on 193 was inconclusive due to the low level of kinetic resolution observed in its reaction with chiral aldehydes.6... 

The limited configurational stability of a-alkylthio organolithiums does not extend to those with benzylic lithium-bearing carbon atoms.112 A Hoffmann test reaction of 233 with 6, for example, gives a 40 60 ratio of stereoisomers 234 whether enantiomerically pure or racemic 6 is used.6 Dynamic NMR experiments2 quantified the barrier to racemisation in 233 as 9.95 kcal mol-1 at 213 K, the temperature at which the diastereotopic CH2 group coalesces. 

Nonetheless, a poor man s Hoffmann test (see section 5.1.1) on 235 indicates that it does possess some degree of configurational stability.112... 

No organolithium a to phosphorus has been shown unequivocally to be configurationally stable. The phosphonamide 279 is configurationally unstable on a macroscopic timescale,128 the phosphine oxide 280 gives racemic products on lithiation even in the presence of an internal quench,129 and in a Hoffmann test the phosphine oxide 281 gave the same ratio of diastereoisomers with either racemic or enantiomerically pure 6.129... 

A Hoffmann test on the lithiated benzylsilane 283 indicated that it had no configurational stability on the timescale of its addition to the aldehyde 6 the same 30 70 ratio was obtained... 

Remarkably, the closely related benzyllithium 304 is configurationally unstable even at -78 °C.138 Transmetallation of 303 (88% ee) at -78 °C gave an organolithium which reacted to give racemic product 305 in the presence or absence of TMEDA. Furthermore, the reaction of the 304-(-)-sparteine complex with each of racemic or enantiomerically pure 2 in a Hoffmann test gave the same 1 1.6 ratio of diastereoisomers. It is not yet clear whether this unexpected difference between 301 and 304 is due to an electronic difference between the naphthyl and phenyl systems, or whether it arises from the difference in steric hindrance, and therefore the dihedral angle between the ring and the amide, in the two compounds. 

The difference between these two mechanisms is the basis of the Hoffmann test, discussed in section 5.1.1. 

The change of ee of a product with varying amounts of electrophile is effectively a variant of the Hoffmann test, for which Beak coined the term poor man s Hoffmann test , because it does not require an enantiomerically pure electrophile. The use of this test to prove configurational stability on the microscopic timescale is described in section 5.1.1. 

A variety of chemical quenching studies provide no evidence of carbon configurational stability in a-lithiated phosphine oxides derived from racemic examples (99) and (100) and from single enantiomers (101) and (102), even under conditions of internal quenching at — 78°C where the timescale for inversion/ rotation is short. An even more soisitive probe for configurational stability is the Hoffmann test. Application of this test to phosphine oxide-stabilised anions has involved comparison of the diastereomeric ratio of products from the reaction of lithiated ethyldiphenyl-phosphine oxide with the racemic phenylala-... 

Hoffmann and coworkers proposed an excellent method for evaluating the configurational stability of the lithium carbanion within the time scale of the rate of the reaction with an electrophile (Hoffmann test) [12]. The Hoffmann test is composed of two experiments. In the first experiment, a racemic organo-lithium compound is reacted with a racemic aldehyde such as 2-(Nd -diben-zylamino)-3-phenylpropanal,the relative rate of formation of the diastereomeric products (k55 kjjj) being estimated by an antUsyn ratio of the products (Fig. 5). 

Fig. 5. The first experiment of the Hoffmann test reaction of a racemic compound with a racemic aldehyde...

The Hoffmann test has also been successfully used to investigate the configurational stability of lithiated diphenylphosphine oxides [113]. It was shown that they are not configurationally stable in tetrahydrofuran (THF) at —78°C on the timescale of their reaction with the aldehyde 193 used to perform the test (on lithiated ethyldiphenylphosphine oxide). 

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