Diisopropylamide and TMP turbo-grignard reagents: A structural rationale for their contrasting reactivities

Article abstract of DOI:10.1002/anie.201000539

(Figure Presented) Turbocharged! A neutral dimeric molecule in crystal form, the diisopropylamido turbo-Grignard reagent (iPr₂N) MgCI· LiCl (see structure; blue N, red O, green Mg, yellow Cl, black C) separates into several charged ate species in dynamic exchange with each other in THF solution as determined by a combination of EXSY and DOSY NMR studies.

Full text of DOI:10.1002/anie.201000539

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DOI: 10.1002/anie.201000539
Turbo-Grignard Reagents
Diisopropylamide and TMP Turbo-Grignard Reagents: A Structural
Rationale for their Contrasting Reactivities**
David R. Armstrong, Pablo Garcꢀa-ꢁlvarez,* Alan R. Kennedy, Robert E. Mulvey,* and
John A. Parkinson
A century on since Grignard won the Nobel Prize in
Chemistry for their development, Grignard reagents
“RMgX” are still widely utilized today and still stand at the
cutting edge of synthetic research. Current innovation centers
on Knochelꢀs exciting 21st century models “turbo-Grignard
reagents” especially those formulated as “R2NMgCl·LiCl”.[1]
Equipped with enhanced kinetic basicity, these commercially
available turbo-Grignard reagents can outperform their
illustrious ancestors by executing magnesiation reactions of
excellent regioselectivity and high functional group tolerance
upon a large number of aromatic and heteroaromatic
substrates. Since the exceptional reactivities of these special
bases must be dictated by cooperative effects between their
different component parts (Li, Mg, R2N, Cl, any solvent
ligands), it is important to understand how these components
organize and interact with each other, both in solid state and
most importantly in solution where they operate. To date,
little structural information has been gathered and, what is
more, only in the solid state through one X-ray crystallo-
graphic study of the TMP (2,2,6 6-tetramethylpiperidide)
chemistry, these results allow a key distinction to be drawn
between TMP-magnesiation reactions performed by these
halide-activated regents and by mixed alkyl-amido formula-
tions that dispense alkali metal mediated magnesiation
(AMMMg).[3]
In a variation of the original literature synthesis,[1c] we
prepared turbo-DA by mixing LDA (iPr2NLi) with magne-
sium chloride in THF.[4] The crystalline form of turbo-DA 2
(60% yield) came from a hexane/THF mixture. Dimeric
aggregation is the main feature of the centrosymmetric
molecular structure of 2 (Figure 1). Its tetranuclear arrange-
ment consists of a central (MgN)2 planar ring, lying orthog-
onal to and separating two (LiCl)2 non-planar outer rings. The
Li atoms carry two THF ligands. All four metal atoms and N
atoms of the amido bridges exhibit distorted tetrahedral
geometries, while the chloro bridges have two-coordinate
bent geometries. The THF ligands, one iPr arm of each DA
ligand, and the chloride atoms Cl2/2a are disordered over two
positions, ruling out discussion of metrical parameters asso-
ciated with them though the connectivity of 2 is unequivocal.
Searching the Cambridge Crystallographic Database[5]
emphasized the general novelty of the turbo-DA structure 2
as no hits were found for an alkali metal/magnesium/DA/
halide composition, and the [Li(m-Cl)2Mg] ring is only
precedented in turbo-TMP 1. Widening the search to
tetranuclear motifs of composition “AM(m-X)2Mg(m-X)2Mg-
(m-X)2AM” (where AM = Li or Na; X = any ligand) revealed
only four hits.[6,7] Poorly soluble in nonpolar solvents, 2 was
dissolved in [D8]THF solution (0.23m)[4] for NMR spectro-
scopic characterization to attempt to reconstruct the actual
conditions employed when turbo-DA is utilized in synthesis.
Two different species labeled 2a and 2b were discernible from
turbo-Grignard
reagent
or
Knochel–Hauser
base
“(TMP)MgCl·LiCl” (turbo-TMP). It exists in the crystal as
the tris(THF)-solvated contact ion pair [(THF)2Li(m-Cl)2Mg-
(THF)TMP] (1).[2] A terminal (TMP)N Mg bond is its salient
À
feature. Here we present a more detailed characterization, in
both the solid state and solution, of “(TMP)MgCl·LiCl” and
its DA (diisopropylamide, iPr2N) analogue, the turbo-
Grignard reagent “(DA)MgCl·LiCl” (turbo-DA). A comple-
mentary combination of X-ray crystallographic and NMR
spectroscopic studies [including diffusion-ordered (DOSY)
and exchange (EXSY) experiments] reveals that both in its
crystalline form, [{(THF)2Li(m-Cl)2Mg(m-DA)}2] (2), and most
significantly in solution turbo-DA differs markedly from
turbo-TMP, enabling a rationalization of their markedly
different observed reactivities.[1c] Furthermore, looking more
generally across the whole field of modern metalation
1
routine ambient-temperature H and 13C{1H} NMR spectra
[*] Dr. D. R. Armstrong, Dr. P. Garcꢀa-ꢁlvarez, Dr. A. R. Kennedy,
Prof. R. E. Mulvey, Dr. J. A. Parkinson
WestCHEM, Department of Pure and Applied Chemistry
University of Strathclyde, Glasgow, G1 1XL (UK)
Fax: (+44)141-548-4787
E-mail: r.e.mulvey@strath.ac.uk
[**] This research was supported by the UK Engineering and Physical
Science Research Council (award nos. EP/F063733/1 and EP/
D076889/1, the Royal Society/Wolfson Foundation (research merit
award to R.E.M.), and the EU (Marie Curie Intra European
Fellowship to P.G.-A). TMP=2,2,6,6-tetramethylpiperidide.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000539.
Figure 1. Molecular structure of [{(THF)2Li(m-Cl)2Mg(m-DA)}2] (2) with
hydrogen atoms and disorder omitted for clarity.[4]
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through two distinct types of DA ligand in a 2:1 ratio (1H
spectrum: 2a d = 3.41/1.32 ppm; 2b d = 2.91/1.02 ppm for
CH/CH3).[4] This complication contrasts with the apparent
simplicity of turbo-TMP 1 which under the same conditions
shows only one type of TMP resonance (1H spectrum: d =
1.57/1.17/1.16 ppm for g-CH2/b-CH2/CH3). The presence of
lithium in 2 was confirmed by a singlet in the 7Li NMR
spectrum (at d = 0.25 ppm),[4] with a similar chemical shift to
that observed for 1 (d = 0.27 ppm). Note that typical reso-
nances of LiTMP and LiDA in [D8]THF are not present in
solutions of 1 and 2, respectively. If 2a and 2b contain lithium
in their structures two distinct resonances are expected at
different chemical shifts, but the possibility of coincident
resonances cannot be discarded. Since a standard of LiCl
(0.23m in [D8]THF solution) reveals a singlet at 0.51 ppm, this
a priori rules out the possibility that 2a and 2b are
monometallic magnesium species and that LiCl is “swim-
ming” free in solution (unless the chemical shift difference is
due to the dielectric constant varying between solutions[8]).
Knochel hypothesized the ionic formula “[Li(THF)4]+-
[iPrMg(THF)Cl2]À” to account for the high reactivity of the
alkyl turbo-Grignard reagent “iPrMgCl·LiCl”,[1a,b] and this
giving [{Li(THF)4}+] and [{(Cl)2Mg(THF)TMP}À], which
have similar sizes, similar results would be seen in the
diffusion experiment. Accurate determination of species sizes
1
7
became necessary to resolve this dilemma. Thus H and Li
diffusion measurements were recorded with internal refer-
ences present. The sizes inferred [expressed in formula weight
(FW) and volume (V)] for different solution concentrations
1
are always in the same range, giving as average: H-TMP
357 Æ 12 gmolÀ1, 297 Æ 9 cm3 molÀ1
;
7Li 326 Æ 12 gmolÀ1,
273 Æ 9 cm3 molÀ1.[4] From these estimated sizes comparisons
can be drawn between these unknowns and plausible species.
Figure 2 depicts some possible candidates with their
respective FW and V values and the error for every
considered structure with respect to the average sizes
predicted through the DOSY study.[4] The contact ion pair
[(THF)2Li(m-Cl)2Mg(THF)TMP] (1) is our starting point.
Dissolved in [D8]THF it can retain its integrity (1A) or
solvent-separate to smaller ionic molecules (1B–1E). The
cation would be a known lithium–THF solvate, most probably
[Li(THF)4]+ (1D). The anion could be a magnesiate type
[(THF)nMg(Cl)2TMP]À (1B, n = 2; 1E, n = 1) or neutral
7
known solvent-separated cation would fit Li NMR data for
2a/2b. As 1H and 13C resonances of 2 appeared broad, hinting
at fluxional processes, a variable-temperature study (from
À788C to 408C)[4] was undertaken. Revealing an even more
complex picture, the former spectra catalog the gradual
decrease in concentration of 2a and 2b and the emergence of
a third species 2c (d = 3.07/1.04 ppm at À788C for CH/CH3 of
DA), which is the major component at À788C. Significantly
7Li spectra show only a singlet throughout the whole temper-
ature window with modest variations in chemical shift (d =
0.25 ppm at 208C; d = 0.30 ppm at À788C). This is again
consistent with one lithium-containing species common to 2a
1
and 2b, and now to 2c. A H-1H EXSY NMR[9] experiment
confirmed dynamic equilibria between all three species.[4] In
1
7
addition, H and Li spectra run at 258C on three different
concentrations (0.46m, 0.23m, and < 0.10m) of 2 in [D8]THF
established that 2a predominates at higher concentrations
whereas 2b predominates at lower concentrations, suggestive
of a possible dimer (2a)–monomer (2b) equilibrium. The
7
same singlet Li resonance was seen during these variable-
concentration studies.[4] To gain further information about the
solution chemistry of 1 and 2, we studied their diffusion
properties using diffusion-ordered NMR spectroscopy
(DOSY). DOSY techniques can be used to identify individual
components of solution mixtures (comparable to chromatog-
raphy in NMR terms), and to estimate their sizes, which are
inversely proportional to their diffusion coefficients (D).[4,10]
1H and 7Li DOSY NMR spectra were recorded in
[D8]THF at À508C. TMP ligand signals (g-CH2, b-CH2,
CH3) show a single cross point with the same diffusion
1
coefficient (D = 1.63 Æ 5 ꢁ 10À10 m2 sÀ1) in H DOSY spectra.
The 7Li DOSY shows also a single aggregate (D = 1.68 ꢁ
10À10 m2 sÀ1).[4] The similar diffusion coefficients obtained in
the 1H and 7Li experiments a priori indicate that proton- and
lithium-containing molecules are linked together into a single
species, possibly the X-ray structure [(THF)2Li(m-Cl)2Mg-
(THF)TMP] (1).[2] However, if solvent separation takes place
Figure 2. Possible species of (TMP)MgCl·LiCl in [D8]THF solution and
errors (in brackets) for every consideration respect to the average FW
and V values predicted through the DOSY study.
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[(THF)2Mg(Cl)TMP] (1C) with concomitant ClÀ swimming
free in solution. Key conclusions reached, using either the FW
or V approach are: firstly, the molecular structure in the
crystal [(THF)2Li(m-Cl)2Mg(THF)TMP] (1) is not retained in
[D8]THF solution as no species near its size (1A) appears in
solution (error range 22–33%); and secondly a solvent-
separated situation described by an appropriate combination
of possible species 1B–1E (error range 1–13%) seems most
probable. The accuracy of the method is not enough to clearly
establish the exact nature of the solution species,[4] but clearly
indicates that lithium- and magnesium-containing species,
although inevitably interacting, do not form strongly con-
tacted ion pairs.
1H and 7Li DOSY NMR spectra were recorded in
[D8]THF at À508C.[4] 1H DOSY spectra show that 2a, 2b,
and 2c have different diffusion coefficients [D(2a) = 1.67 ꢁ
10À10 m2 sÀ1
;
D(2c) = 1.91 ꢁ 10À10 m2 sÀ1
;
D(2b) = 2.08 ꢁ
10À10 m2 sÀ1] which indicates a relative size sequence of 2a @
2c > 2b. 7Li DOSY, in accordance with its simplicity, shows a
single aggregate (D = 2.00 ꢁ 10À10 m2 sÀ1), suggesting that its
size is similar to that of 2b or 2c but much smaller than that of
2a.[4] The fact that 1H DOSY shows three different DA-
containing species and 7Li DOSY just one lithium aggregate,
indicates that at least two DA–magnesium complexes do not
contain lithium in their compositions, making again solvent
separation most plausible. The use of internal standards
became necessary to obtain more information about the
complicated nature of (DA)MgCl·LiCl in THF solution so the
procedure carried out with the TMP complex was repeated.
FW and V values for the “1H-DA” and “7Li” species lie in the
same range at different concentrations. The averages values
are: 1H-DA(2a) = 543 Æ 13 gmolÀ1, 433 Æ 9 cm3 molÀ1
;
1H-
DA(2c) = 404 Æ 16 gmolÀ1,
(2b) = 343 Æ 11 gmolÀ1,
332 Æ 12 cm3 molÀ1
;
1H-DA-
287 Æ 8 cm3 molÀ1
;
7Li = 340 Æ
40 gmolÀ1, 285 Æ 30 cm3 molÀ1.[4] Figure 3 depicts some possi-
ble molecules that can form in a [D8]THF solution of
(DA)MgCl·LiCl (considering what would require the least
reorganization from the solid-state structure) with their
respective FW and V values and the error for every
considered structure respect to the average sizes predicted
through the DOSY study.[4] If the contacted ion-pair
[{(THF)2Li(m-Cl)2Mg(m-DA)}2] (2) dissolved in [D8]THF
retains its integrity, a species with a FW of 725.28 gmolÀ1
(2A) should be visible in the second dimension; however, the
heaviest species FW predicted is only 543(13) gmolÀ1, which
Figure 3. Possible species of (DA)MgCl·LiCl in [D8]THF solution with
1
errors (in brackets respect to 2a/2c/2b when applicable) respect to
average FW and V values predicted through the DOSY study.
implies a 25% error using H DOSY data. Also considering
the heaviest and unique lithium species in solution has a
predicted FW of 340(40) gmolÀ1, the error of considering the
7
existence of 2A would be around 50% from Li DOSY. The
D–V approach exhibits the same results. Thus consistent with
the TMP derivative, it appears that the solid-state structure
[{(THF)2Li(m-Cl)2Mg(m-DA)}2] (2) is not retained in [D8]THF
solution. A solvent-separated situation implies the existence
of a THF-solvated lithium cation species, most probably
[Li(THF)4]+ (2F) although a higher THF solvation cannot be
ruled out. Anionic counterions range from dimeric (2B–2D),
in which different THF solvation and ClÀ coordination are
considered, to monomeric 2E, 2G and 2H. The method is not
accurate enough[4] to unequivocally establish the exact nature
of 2a, 2b, and 2c but clearly indicates that 2a fits the dimer
category and 2b is a monomer (as suggested by the concen-
tration study), and 2c is in an intermediate situation. They all
are “DAMgCl”-containing species in equilibria affected by
concentration and temperature.
These results show how changing the steric bulk and
electronic properties of the amide controls not only the turbo-
Grignard bases’ structural features (in solid state and
solution), but also changes strongly their reactivity character-
istics. For example, whereas (TMP)MgCl·LiCl selectively
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magnesiates ethyl-3-chlorobenzoate in the C2 position,[1d,2]
with (DA)MgCl·LiCl only addition–elimination is observed.[4]
Although not definitive about the exact solution nature of
turbo-TMP and turbo-DA in THF, these NMR studies clearly
indicate their solid-state structures are not retained. Com-
pared against the uniformity of a single solution species with a
2006, 45, 2958; d) W. Lin, O. Baron, P. Knochel, Org. Lett. 2006,
8, 5673; e) C. J. Rohbogner, S. H. Wunderlich, G. C. Clososki, P.
Knochel, Eur. J. Org. Chem. 2009, 1781; f) A. H. Stoll, P. Mayer,
P. Knochel, Organometallics 2007, 26, 6694; g) G. C. Clososki,
C. J. Rohbogner, P. Knochel, Angew. Chem. 2007, 119, 7825;
Angew. Chem. Int. Ed. 2007, 46, 7681; h) J. Rohbogner, G.
Clososki, P. Knochel, Angew. Chem. 2008, 120, 1526; Angew.
Chem. Int. Ed. 2008, 47, 1503; i) M. Mosrin, P. Knochel, Org.
Lett. 2008, 10, 2497; j) F. M. Piller, P. Knochel, Org. Lett. 2009,
11, 445; k) L. Melzig, C. B. Rauhut, P. Knochel, Chem. Commun.
2009, 3536; l) M. Mosrin, T. Bresser, P. Knochel, Org. Lett. 2009,
11, 3406.
À
solitary terminal Mg N(amido) bond, the DA turbo-base
exhibits a dynamic mixture of species, complicated by the
presence of both bridging and terminal amido ligands, which
in combination with the inherent lower basicity of DA versus
TMP can explain, at least in part, the different observed
reactivities of turbo-DA and turbo-TMP. This established
solvent-separated nature of these chloride-based magnesiat-
ing agents distinguishes them from the contact ion-pair
arrangements generally found for related alkyl amido species
[2] P. Garcꢂa-ꢃlvarez, D. V. Graham, E. Hevia, A. R. Kennedy, J.
Klett, R. E. Mulvey, C. T. OꢀHara, S. Weatherstone, Angew.
Chem. 2008, 120, 8199; Angew. Chem. Int. Ed. 2008, 47, 8079.
[3] a) R. E. Mulvey, Acc. Chem. Res. 2009, 42, 743; b) R. E. Mulvey,
F. Mongin, M. Uchiyama, Y. Kondo, Angew. Chem. 2007, 119,
3876; Angew. Chem. Int. Ed. 2007, 46, 3802; c) R. E. Mulvey,
Organometallics 2006, 25, 1060.
such as [(TMEDA)Na(m-TMP)(m-nBu)Mg(TMP)] (3),
a
mitigating factor being the former are used in THF solution,
while the latter are generally used in hydrocarbon solution.
Therefore distinct mechanisms must be open to each type of
Mg base. Intermolecular processes not directly involving the
alkali metal should be common with the former, whereas
intramolecular processes in which the alkali metal could act as
a Lewis acidic coordination point for an incoming aromatic
substrate within a pre-magnesiation complex are probable
with the latter. This distinction may explain why turbo-
Grignard reagents tend to manifest their enhanced magne-
siating power in usual ortho positions (conforming to directed
ortho-metalation, DoM principles),[11] whereas favorable
stereochemical dispositions in base–substrate complexes
enable 3 to perform deprotonations in extraordinary posi-
tions, typified by the meta-magnesiation of toluene.[12]
[4] See Supporting Information for full experimental and crystallo-
graphic details.
[5] CSD version 5.31 (Updated Nov 2009). See also, F. H. Allen,
Acta Crystallogr. Sect. B 2002, 58, 380.
[6] S. C. Cole, M. P. Coles, P. B. Hitchcock, Organometallics 2004,
23, 5159.
[7] J. Garcꢂa-ꢃlvarez, D. V. Graham, E. Hevia, A .R. Kennedy,
R. E. Mulvey, Dalton Trans. 2008, 1481.
[8] For example: T. Takayama, I. Ando, T. Asakura, Bull. Chem.
Soc. Jpn. 1989, 62, 1233.
[9] For example: K. G. Orrell, Annu. Rep. NMR Spectrosc. 1999, 37,
1 – 74.
[10] For recent DOSY reviews see: a) D. Li, I. Keresztes, R. Hopson,
P. Williard, Acc. Chem. Res. 2009, 42, 270; b) A. Macchioni, G.
Ciancaleoni, C. Zuccaccia, D. Zuccaccia, Chem. Soc. Rev. 2008,
37, 479; c) B. Antalek, Concepts Magn. Reson. Part A 2007, 30,
219.
[11] For key DoM reviews see: a) “The Directed ortho Metalation-
Cross Coupling Nexus. Synthetic Methodology for Aryl-Aryl
and Aryl-Heteroatom-Aryl Bonds”: E. Anctil, V. Snieckus in
Metal-Catalyzed Cross-Coupling Reactions, 2nd ed. (Eds.: F.
Diederich, A. de Meijere), Wiley-VCH, Weinheim, 2004,
pp. 761 – 813; b) “The Directed ortho Metalation Reaction. A
Point of Departure for New Synthetic Aromatic Chemistry”:
C. G. Hartung, V. Snieckus in Modern Arene Chemistry (Ed.: D.
Astruc), Wiley-VCH, New York, 2002, pp. 330 – 367.
[12] P. C. Andrikopoulos, D. R. Armstrong, D. V. Graham, E. Hevia,
A. R. Kennedy, R. E. Mulvey, C. T. OꢀHara, C. Talmard, Angew.
Chem. 2005, 117, 3525; Angew. Chem. Int. Ed. 2005, 44, 3459.
Received: January 29, 2010
Published online: March 29, 2010
Keywords: amides · DOSY NMR spectroscopy ·
.
Grignard reagents · metalation · structure elucidation
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Angew. Chem. Int. Ed. 2004, 43, 3333; b) A. Krasovskiy, B. F.
Straub, P. Knochel, Angew. Chem. 2006, 118, 165; Angew. Chem.
Int. Ed. 2006, 45, 159; c) A. Krasovskiy, V. Krasovskaya, P.
Knochel, Angew. Chem. 2006, 118, 3024; Angew. Chem. Int. Ed.
3188
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