Angewandte
Chemie
[
8]
Abstract: Lithium diisopropyl amide (LDA) is a very prom-
inent reagent that plays a key role in organic synthesis, serving
as a base par excellence for a broad range of deprotonation
reactions. However, the state of aggregation in solution in the
absence of donor bases was unclear. In this paper we solved
this problem by employing DOSY NMR experiments based on
a newly elaborated external calibration curve (ECC) approach
with normalized diffusion coefficients.
ingly important for identifying species in solution. The
DOSY experiment separates NMR signals of species accord-
[9]
ing to their diffusion coefficients. This is why a polymer
chemist has called this technique “chromatography by
NMR”. However, there is no simple relationship between
the diffusion coefficient and the molecular weight (MW). A
number of empirical methods for relating diffusion coeffi-
[
10]
[
11]
cients to the MW have been proposed. The empirically
derived power law [Eq. (1)] that correlates the MW and the
[12]
A
lthough lithium diisopropyl amide (LDA, Scheme 1) is one
a
of the most common and widely used non-nucleophilic
D ¼ K Á MW
ð1Þ
[
1]
Brønsted bases its donor-base-free solid-state crystal struc-
ture was only determined in 1991. It consists of an infinite
[
2]
diffusion coefficient is particularly effective, but is restricted
to a specific class of compounds. The polymer community
in particular has applied it to estimate the MW distribution of
[
13]
[
13]
polymer solutions such as globular proteins, oligosacchar-
[
14]
[15]
[16]
ides,
polyethyleneoxides,
and denatured peptides
in
various solvents. Recently we developed a power law based
external calibration curves (ECC) for small molecules. These
ECCs facilitate the determination of accurate MWs for small
molecules with different geometries, independent of NMR-
specific properties and differences in temperature or viscos-
[
17]
1
ity. Here we describe H DOSY NMR ECC-MW determi-
nations of LDA solvated in [D ]toluene over a temperature
8
range of À75 88 C to 1008C. We will show that the aggregation
state of LDA is highly temperature dependent and that the
trimeric and tetrameric LDAs are the most populated species
in toluene solution.
Scheme 1. LDA in the solid state and in toluene solution.
LDA is polymeric in the solid state and shows little
solubility in toluene. The highest concentrations that we could
observe at room temperature (RT) were in the range of 7–
7
helical chain with four units per turn in the helix. In solution
in all monodentate donating solvents LDA exists as a single
15 mm. The Li NMR spectra of these highly dilute LDA
[
18]
solutions at RT show one broad signal at 2.81 ppm. In the
[3]
1
observable aggregate—the solvated dimer. That makes
LDA an ideal template for studying organolithium reactiv-
H NMR spectrum two sets of two main signals corresponding
to the a-CH (3.12 ppm and 3.01 ppm) and CH3 groups
(1.14 ppm and 1.11 ppm) are present. A third compound was
also evidenced by an additional a-CH signal at 3.19 ppm, but
with very low intensity (Figure 1A). Due to its poor intensity
we were not able to determine the diffusion coefficient of this
third compound at RT, but although the other two main
signals at 3.12 ppm and 3.01 ppm show some overlap, we
could measure their self-diffusion.
[4]
ity and is why LDA is one of the best examined lithium
[
5]
amides. Collum et al. provided deeper insights into LDA-
mediated reaction mechanisms, solution kinetics, structure–
[
6]
reactivity relationships, reaction rates, and selectivity. How-
ever, the aggregation of LDA in donor-base-free solvents was
still unclear. In 1991 Kim and Collum et al. investigated
6
6
15
6
15
[
Li]LDA and [ Li, N]LDA in hexane by Li and N NMR
[
6b]
spectroscopy.
They observed a mixture of three major
The ECC-MW results (Table 1B) agree best with a trimer
À1
cyclic oligomers and suggested that they correspond to cyclic
dimers, trimers, and higher oligomers. Unfortunately they
were not able to quantify these observations because “a severe
overlap renders the effort required for a detailed study
1 in Scheme 1 (MWdet = 318 gmol , MW = 1%) and a tetra-
err
À1
[19]
mer 2 (MWdet = 390 gmol , MW = 9%).
The method
err
employs normalized diffusion coefficients. Taking the shape
of the molecules into account enables accurate MW predic-
tions with a maximum error of Æ 9%. The addition of
multiple internal references is not necessary. One internal
reference (which can also be the solvent) is sufficient. If the
solvent signal is not accessible, 16 other internal standards
[6b]
unjustifiable”.
In addition to NMR and mass spectrometry experiments
conducted with isotopically labeled compounds, diffusion-
[
7]
ordered NMR spectroscopy (DOSY) has become increas-
(aliphatics and aromatics) are available that avoid problems
with signal overlap. This method is independent of NMR
spectrometer parameters and variations in temperature or
viscosity and hence provides an easy and robust method to
[
*] M.Sc. R. Neufeld, Dr. M. John, Prof.Dr. D. Stalke
Institut für Anorganische Chemie, Georg-August-Universität
Tammannstrasse 4, 37077 Gçttingen (Germany)
E-mail: dstalke@chemie.uni-goettingen.de
[
17]
determine accurate MWs. Careful integration of the two
[**] DOSY=diffusion-ordered NMR spectroscopy.
signals reveals that 1 and 2 exist together in a ratio of 2:1 at
+
258C. It is also evident that dimers, like those anticipated by
Kim, for example, are not present in this mixture (MWerr
=
Angew. Chem. Int. Ed. 2015, 54, 6994 –6998
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim