Solution Structure of Turbo-Hauser Base TMPMgCl?LiCl in [D8]THF

Article abstract of DOI:10.1002/chem.201601494

Turbo-Hauser bases are very useful and highly reactive organometallic reagents in synthesis. Especially TMPMgCl?LiCl 1 (TMP=2,2,6,6-tetramethylpiperidide) is an excellent base for converting a wide range of (hetero)aromatic substrates into highly function

Full text of DOI:10.1002/chem.201601494

DOI: 10.1002/chem.201601494
Communication
&
Organometallic Chemistry |Hot Paper|
Solution Structure of Turbo-Hauser Base TMPMgCl·LiCl in
D ]THF**
[
8
[a]
Roman Neufeld and Dietmar Stalke*
Abstract: Turbo-Hauser bases are very useful and highly
reactive organometallic reagents in synthesis. Especially
TMPMgCl·LiCl 1 (TMP=2,2,6,6-tetramethylpiperidide) is an
excellent base for converting a wide range of (hetero)aro-
matic substrates into highly functionalized compounds
with a broad application in organic synthesis. The knowl-
edge of its structure in solution is of essential importance
to understand the extraordinary reactivity and selectivity.
However, very little is known about the aggregation of
this prominent reagent in solution. Herein, we present the
THF-solution structure of 1 by employing our newly ela-
borated DOSY NMR method based on external calibration
curves (ECC) with normalized diffusion coefficients.
The regio- and stereoselective deprotonation and functionali-
zation of aromatic compounds using amide bases or alkyl or-
ganometallics is one of the most versatile and applied synthet-
ic transformations. As a drawback, strong organic bases such
as alkyl amides require relatively low temperatures (À788C)
and show competing addition reactions (e.g. Chichibabin reac-
tions). A better selectivity was achieved by Hausers’ magnesi-
[
1]
um bases R NMgX. These are analogues to Grignards’ re-
2
agents, but instead of an alkyl substituent, the magnesium
halide is connected to an amido moiety. Unfortunately, most of
them show a poor solubility in THF and, as a consequence, the
metalation rates are very slow. It is well-known that numerous
[
2]
metallic salts are more soluble when LiCl is present. This fea-
ture has led to the design of LiCl-solubilized TMPMgCl·LiCl
1
and its less bulky Turbo analogue DAMgCl·LiCl 2 (DA=diiso-
Figure 1. a) Typical notation of Turbo-Hauser bases TMPMgCl·LiCl 1 and
DAMgCl·LiCl 2. b) The most plausible solution structures of 1 and 2 in
[D ]THF solution.
8
[
3]
propylamide, Figure 1a). Equipped with enhanced kinetic ba-
sicity, these commercially available reagents display a high re-
activity even at room temperature (RT) as well as excellent re-
gioselectivity and high functional-group tolerance for a large
[
8]
[
4]
number of aromatic and heteroaromatic substrates. Although
there is a great deal of information on the utility of these re-
agents, very little is known regarding the nature of Turbo-
oligomers to furnish magnesiate character to the Grignard re-
+
agent by
a solvent-separated ion pair (SSIP) [Li(thf)4]
À [6]
[RMg(thf)Cl ] . At least, in the solid state the Turbo-Hauser
2
[
3]
[7]
[5]
Hauser base 1 in solution. Knochel et al., Garcꢀa-ꢁlvarez and
Mulvey et al. suggested that added LiCl deaggregates RMgX
bases TMPMgCl·LiCl 1C and DAMgCl·LiCl 2A (Figure 1b)
supported the existence of a contact ion pair (CIP). Recently,
we showed that redissolved crystals of 2A do not form SSIPs
[
5]
[9]
[a] Dr. R. Neufeld, Prof. Dr. D. Stalke
in THF solution either. Instead, the dimeric crystal structure
A equilibrates with its monomeric counterpart 2C at room
Institut fꢀr Anorganische Chemie, Georg-August-Universitꢁt
Tammannstraße 4, 37077 Gçttingen (Germany)
E-mail: dstalke@chemie.uni-goettingen.de
2
temperature. In both structures, LiCl co-coordinates to both
Hauser bases. Lowering the temperature triggers the formation
of more oligomers in the equilibrium. First LiCl gets separated
from 2A and forms a well-known [(thf) Li(m-Cl) Li(thf) ]-dimer
[
**] TMP=2,2,6,6-tetramethylpiperidide.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201601494.
2
2
2
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[
10]
(
(
Li1). While the Hauser base keeps the dimeric aggregation
2B) its interaction with Li1 inhibits a Schlenk-equilibrium-
a number of smaller molecules (1C*–1E, Figure 1b). LiCl can
either coordinate to the magnesium amide or dissociate as
[10]
driven transformation to the homoleptic side and the antici-
pated formation of DA Mg and MgCl . Since both magnesium
a well-known [(thf) Li(m-Cl) Li(thf) ] dimer Li1. A solvent-sepa-
2 2 2
+
rated ion pair (SSIP) containing [Li(thf)4] Li2 would promote
the formation of an ate-complex 1E in which two chloride ions
coordinate a single magnesium cation. From the crystal struc-
ture of 1 it is known that the lithium cation is located at an
2
2
amides 1 and 2 show a different reactivity and regioselectivi-
[
3]
ty, it is very important to understand how TMPMgCl·LiCl 1 or-
ganizes and interacts, especially in solution. The method of
choice to identify species in solution is NMR spectroscopy.
Garcꢀa-ꢁlvarez and Mulvey et al. analyzed crystals of 1 in
average distance of 4.68 ꢄ to the closest CH -protons of the
3
[7]
TMP ligand. This relatively close distance should be detecta-
[
5]
1
7
[
D ]THF solution by diffusion-ordered spectroscopy (DOSY)
ble in a H– Li-HOESY experiment for which the structure is re-
8
[13e]
and the diffusion coefficient formula weight (D-FW) analysis
tained in solution.
For NMR spectroscopic measurements,
[
11]
that was pioneered by Li and Williard et al. This method is
based on internal calibration curves (ICC), for which many in-
ternal standards that may interfere with the reactive metal
complexes are required. Because of peak overlap problems the
we used diluted solutions of 1 (20 mm) by dissolving the crys-
[17]
1
tals in [D ]THF. The H NMR spectra of 1 show at all tempera-
8
tures (258C to À758C) only one single type of TMP ligand (d=
1.19/1.22/1.62 ppm for CH /b-CH /g-CH, Figure 2), whereas the
3
2
[
12]
[18]
authors had to use inappropriate internal standards, so the
molecular weight (MW) determination was prone to a relatively
high error of approximately Æ30%. Consequently Garcꢀa-ꢁlvar-
ez and Mulvey et al. stated that they were not able to “clearly
Turbo-Hauser base 2 displays several oligomers. Indeed the
[
5]
establish the exact nature of the solution species”. Predomi-
nantly it could not be established whether or not lithium chlo-
ride is co-coordinated to the magnesium amide. In the end, it
was concluded that a SSIP situation appeared to be the most
feasible. In the following section we will shed light on the solu-
tion structure of 1 and prove that LiCl does indeed coordinate
to Turbo-Hauser base 1. Recently, we developed an advanced
DOSY NMR technique that enables the identification of reac-
[
13]
tive species in solution. This method for accurate MW-deter-
mination rests on external calibration curves (ECC) with nor-
malized diffusion coefficients. Only one internal reference is
sufficient and the addition of multiple internal references is
dispensable. Furthermore, it is independent of diversities in
temperature and viscosity and offers an easy and robust ap-
proach to determine accurate MWs in THF solution with an
1
Figure 2. Superposition of H NMR spectra of redissolved crystalline 1 in
[D ]THF at various temperatures.
8
1
7
H– Li-HOESY-spectra at all temperatures display a cross peak
[
14]
error of less than Æ9%. Employing this method, we were al-
between lithium and the CH groups confirming the lithium
3
ready able to characterize the complex oligomeric mixture of
coordination to the magnesium amide (see Figures S3 and S4
[
15]
[19]
7
lithium diisopropylamide (LDA) in toluene solution and the
in the Supporting Information). The Li NMR spectra show
one singlet at about d=0.2 ppm in the whole temperature
range (see Figure S2 in the Supporting Information). The pres-
ence of remaining LiTMP can be excluded since it resonates at
[9]
structure of DAMgCl and DAMgCl·LiCl 2 in [D ]THF solution.
8
In the current paper, we describe DOSY-ECC-MW-determina-
tions of the TMP-Turbo-Hauser base TMPMgCl·LiCl 1 in [D ]THF
8
[20]
solution.
d=0.7 (monomer) or at 1.3 ppm (dimer), respectively. Addi-
+
Primarily it seems advisable to a priori rationalize which spe-
cies are feasible to be present in the solution of 1. The most
obvious question to be addressed in s-block organometallics
of course is the amount of coordinating THF molecules to be
present in the solution structure of 1. Even from a vast
number of solid-state structures it is known that polar solvents
like THF are necessary to coordinate such highly ionic com-
tionally, the lithium cation [Li(thf)4] Li2 in a SSIP can also be
excluded to be present at significant concentrations since it is
[21]
known to resonate at negative field (d=À1.1 ppm), curtail-
ing the plausible present species to the lithium-containing
dimer 1A and the monomers 1C/1C*. Both aggregates should
1
clearly be distinguishable by DOSY NMR spectroscopy. The H
7
and Li-DOSY-ECC-MW-determination of 1 gives a MW of
MWdet =403 gmol for the H and 387 gmol for the Li nu-
[
7]
À1
1
À1
7
pounds. Following the preparation of Mulvey et al. we syn-
[22]
thesized the Turbo-Hauser base 1 by reaction of equimolar
cleus (Figure 3). This low MW discriminates both the lithium
LiTMP with a suspension of MgCl in THF and then stirring the
free aggregates 1B (MW =26%), 1D (MW =À17%), 1E
2
err
err
[23]
mixture for one day at room temperature. Removing the sol-
vent in vacuo and recrystallization (2ꢃ) in a 1:1 THF/hexane
mixture at À458C afforded 1 as colorless crystals in 17%
(MW =À31%), and also dimeric 1A (MW =48%). Most in-
err
err
terestingly, the crystal structure 1C does not keep its full integ-
rity in [D ]THF solution reflected by an unacceptably high error
8
[
16]
À1
À1
yield. A redissolved crystal of 1 in net THF could on the one
hand retain its solid state structure (1C) or even aggregate fur-
ther to combine to dimers (1A, 1B) as well as dissociate to
of the MW (MWcalcd =459 gmol , MW =403 gmol , MW =
det err
12%). The smaller contact ion pair 1C* derived from 1C by
the loss of a single THF molecule matches best the determined
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Our investigations confirm that lithium chloride
indeed co-coordinates to the magnesium amides in
[9]
solution as observed in the Turbo-Hauser base 2.
A
detectable population of the solvent separated lithi-
um cation Li2 can also be excluded for Turbo-Hauser
À1
À1
base 1 (MWcalcd =295 gmol , MW =387 gmol ,
det
MW =À31%). Changing the steric bulk and the
err
electronic properties of the amide strongly controls
the structural features, both in the solid state as well
as in solution. While 1 is a monomer in the solid
state and in solution, 2 is a dimer in the crystal struc-
ture and forms predominately dimeric aggregates in
[9]
THF solution. The deviation in the aggregation
state and steric demand is also reflected in the differ-
[3]
[5]
ent reactivity and regioselectivity of both Turbo-
Hauser bases (Scheme 1). From our measurements,
the different reactivities can be rationalized as fol-
lows: The TMP ligand in TMPMgCl·LiCl 1 is bulky
enough to prevent dimerization (Figure 3) and to
promote a LiCl solubilized monomer 1C*. Similarly
the appreciable bulk provided by the fixed methyl
groups facilitates the cleavage of a labile THF ligand
and induces an unsaturated magnesium site. In DA-
MgCl·LiCl 2 the rigid TMP ligand is replaced by two
floppy diisopropyl groups and the methyl groups are
not fixed in a static position relative to the metal.
This flexibility permits both a direct THF coordination
at the Mg cation and a dimerization of the lithium-
stabilized monomer 2C to form the tetranuclear
dimer 2A. The latter is, at high concentrations, the
[5,9]
main aggregate in solution.
This would also ex-
plain the limited solubility of dimeric 2 in THF (0.6m)
compared to the monomeric TMP-Turbo-Hauser base
1
(1.2m). In general, monomeric species display the
most active kinetic species in organolithium chemis-
[27]
try. This could explain why reactions of the TMP-
Turbo-Hauser base are much faster than that of di-
meric DA-Turbo-Hauser base (Scheme 1a). In addi-
tion, we suggest that the highly regioselective ortho
deprotonation reactions could stem from a sufficient
1
7
[8]
Figure 3. H- and Li-DOSY-ECC-MW-determination of crystalline 1 redissolved in
[
14]
[D
8
]THF (20 mm). The accuracy of this method is in the range of MWerr ꢀ Æ9%.
À1
À1
[28]
MW (MWcalcd =387 gmol , MW =403 gmol , MW =À4%).
complex-induced proximity effect (CIPE) between the bimet-
det
err
Mulvey et al. already mentioned the labile THF coordination at
allic aggregate 1C* and the functionalized (hetero)aromatic
substrates 7 and 8 in Scheme 2. Compared to the TMP ligand,
the diisopropyl amide ligand provides lower steric hindrance
and facilitates the approach to the carbonyl function (see the
reaction in Scheme 1b). Further, due to the lower basicity (DA
1
1
C as the expected integrated H NMR intensity. THF/amide
decreases from 3:1 to 2:1 when the crystals are dried in
[
7]
vacuo. From this they concluded that the powerful regiose-
lective magnesiating ability of 1 might be a consequence of
a coordinately unsaturated Mg that “could facilitate the pre-co-
ordination of the functionalized aromatic substrate prior to
[29]
vs. TMP ligand: pK =34 vs 38) the addition to the nucleo-
a
philic carbon center is favorable (thermodynamic product). In
contrast, due to the high steric demand of the TMP ligand and
its higher basicity, the deprotonation reaction is favored over
the addition reaction (kinetic product).
[
7]
magnesiation”. Our DOSY-ECC-MW-determination fully sup-
ports this hypothesis. The labile THF ligand at the magnesium
atom could be a result of steric overload from the rigid TMP
[24]
ligand. Searching the Cambridge Crystallographic Database
emphasizes Mg typically to be coordinated by four to six li-
gands. Enlarging the bulk of the various substituents, however,
results also in 3-coordinated magnesium amides. This is often
Experimental Section
Dry [D ]THF stored with 4 ꢄ molecular sieves under argon was
8
[
25]
the case when bulky SiMe groups and especially when TMP
used. The NMR samples were prepared by dissolving crystalline
1 and the DOSY reference 1-phenylnaphtaline (PhN) in equimolar
3
[
26]
ligands are involved.
Chem. Eur. J. 2016, 22, 1 – 6
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Communication
Acknowledgements
We acknowledge funding from the Danish National Research
Foundation (DNRF93) funded by Centre for Materials Crystal-
lography (CMC).
Keywords: diffusion · metallation · organometallic chemistry ·
NMR spectroscopy · reactive species
[
[
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[
1
1
[
[
[
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28]
Scheme 2. Complex-induced proximity effect (CIPE): Proposed transition
states for 1C* in some regioselective ortho deprotonation reactions with
functionalized (hetero)aromatic compounds. FG=coordinating functional
group; X=heteroatom.
8079–8081; Angew. Chem. 2008, 120, 8199–8201.
8] Deuterated species diffuse like their protonated counterparts. This is
À1
why we used MWcalc(THF)=72.11 gmol in the calculation of all THF
coordinated species. For more information see ref. [13].
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8
amide species were normalized to the fixed diffusion value of the
reference PhN (logDref,fix(PhN)=À8.8812; for more information see
the Supporting Information). NMR spectra were recorded on
a Bruker Advance 400 spectrometer equipped with an obverse
broadband probe with z-axis gradient coil with maximum gradient
[
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9
2
À1
strength of 57 Gcm . All spectra were acquired using 5 mm NMR
[
12] The error of the DOSY molecular weight (MW) analysis depends highly
on the geometry of the used references as well on that of the analyte
(see ref. [14]). Hauser bases have an ellipsoidal geometry. Therefore el-
lipsoid references should be used for an accurate MW analysis. Howev-
er, the authors from ref. [5] used references with different geometries
tubes, which were not spinning during the measurements. All
DOSY experiments were performed using a double-stimulated
echo sequence with bipolar gradient pulses and three spoil gradi-
[30]
ents with convection compensation (dstebpgp3s). The duration
of the magnetic field pulse gradients was adjusted for every tem-
perature in a range of d/2=400–3500 ms. The diffusion time was
D=0.1 s. The delay for gradient recovery was 0.2 ms and the eddy
current delay 5 ms. In each PFG NMR experiment, a series of 16
spectra on 32 K data points were collected. The pulse gradients
were incremented from 2 to 98% of the maximum gradient
strength in a linear ramp. After Fourier transformation and baseline
correction, the diffusion dimension was processed with the Top-
spin 3.1 software. Diffusion coefficients, processed with a line
broadening of 2 Hz, were calculated by Gaussian fits with the T1/
T2 software of Topspin.
(
spherical, ellipsoidal, and flat discs) that dramatically decreased the ac-
curacy of the MW determination.
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Communication
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[
16] The crystal structure was proven by X-ray diffraction.
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17] The herein used external calibration curves work best with diluted solu-
tions; this is why we chose 20 mm solutions of crystalline 1C, consider-
ing the loss of one molecule of THF of 1C in the drying process.
18] A small amount of protonated amine TMP(H) is also present in solution.
The ECC-MW-determination predicts an accurate MW at temperatures
[
between
0
and À758C (in av.: MWcalcd =141 gmolÀ1
,
MWdet =
À1
140 gmol , MWerr =1%). Interestingly, at room temperature, the MW is
À1
slightly overestimated (MWdet =167 gmol , MWerr =À18%), indicating
an exchange between the amide and the amine. Anyway, this interac-
tion is neglectible at temperatures below 08C, see Table S4 in the Sup-
porting Information.
[
[
[
19] Similar results were observed for Hauser base 2, see ref. [9].
20] P. Renaud, M. A. Fox, J. Am. Chem. Soc. 1988, 110, 5702–5705.
21] C. Elschenbroich, F. Hensel, H. Hopf, Organometallchemie, Vol 6, B. G.
Teubner Verlag, Wiesbaden, 2008.
22] All MWdet values are dispayed for each species as an average value, de-
rived from DOSY-ECC-MW measurements at different temperatures, see
Tables S5 and S6 in the Supporting Information.
[28] M. C. Whisler, S. MacNeil, V. Snieckus, P. Beak, Angew. Chem. Int. Ed.
2004, 43, 2206–2225; Angew. Chem. 2004, 116, 2256–2276.
[29] H. Ahlbrecht, G. Schneider, Tetrahedron 1986, 42, 4729–4741.
[30] a) A. Jerschow, N. Mꢆller, J. Magn. Reson. 1997, 125, 372–375; b) A. Jer-
schow, N. Mꢆller, J. Magn. Reson. 1996, 123, 222–225.
[
[
23] The deviation is calculated by MWerr =[1ÀMWdet/MWcalc]·100%, in which
MWdet is the experimentally determined and MWcalcd is the calculated
molecular weight.
Received: March 31, 2016
Published online on && &&, 0000
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
5
ꢂ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
Go turbo! Turbo-Hauser bases are very
useful and highly reactive organometal-
lic reagents in synthesis. However, very
little is known about the aggregation of
TMPMgCl·LiCl in solution. Herein, we
present the THF-solution structure of
1 by employing our newly elaborated
DOSY NMR method based on external
calibration curves (ECC) with normalized
diffusion coefficients (see graphic).
&
Organometallic Chemistry
R. Neufeld, D. Stalke*
& – &&
&
Solution Structure of Turbo-Hauser
Base TMPMgCl·LiCl in [D ]THF
8
&
&
Chem. Eur. J. 2016, 22, 1 – 6
www.chemeurj.org
6
ꢂ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!